CN106715456A - Lymph directing prodrugs - Google Patents

Lymph directing prodrugs Download PDF

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Publication number
CN106715456A
CN106715456A CN201580053370.4A CN201580053370A CN106715456A CN 106715456 A CN106715456 A CN 106715456A CN 201580053370 A CN201580053370 A CN 201580053370A CN 106715456 A CN106715456 A CN 106715456A
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compound
acid
alkyl
pharmaceutically active
active agents
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CN106715456B (en
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C·波特
J·辛普森
N·特里瓦斯基斯
T·魁奇
韩思飞
胡罗娟
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Monash University
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Monash University
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Priority claimed from AU2014903148A external-priority patent/AU2014903148A0/en
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Priority to CN202311047800.4A priority Critical patent/CN117088931A/en
Priority to CN202011362790.XA priority patent/CN112430250A/en
Priority to CN202311048091.1A priority patent/CN117164657A/en
Publication of CN106715456A publication Critical patent/CN106715456A/en
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C07J1/0025—Esters
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C07J1/0029—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
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    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The present invention relates to compounds and their uses, in particular, compounds in the form of prodrugs that promote transport of a pharmaceutical agent to the lymphatic system and subsequently enhance release of the parent drug.

Description

Orient the prodrug of lymph
Invention field
The present invention relates to the compound of prodrug forms, pharmaceutically active agents are particularly promoted to be transported to lymphatic system and then increase The compound of strong parent drug release.
Background of invention
Lymphatic system is by being distributed in the specialization network structure of the blood vessel close to vascular system, tubercle and the lymphoid tissue of whole body Composition.Lymphatic system plays numerous keys in immune response, isohydria, nutritious compound absorption, lipid homeostasis and metastases Effect.Due to the unique anatomical and physiologic character of lymphatic system, by targeting drug delivery to lymphatic system and by lymphatic system Targeting drug delivery suggestion is improvement pharmacokinetics and the means of pharmacodynamic profiles.Lymph drug transport has spends generation by avoiding head Thank to raising oral administration biaavailability, change systemic drug disposal and strengthen to lymph or the pathology of cell mediated The efficiency of (for example lymthoma, leukaemia, lympha tumour transfer, autoimmune disease, lymph stop infection and transplant repulsion) Potential.
For medicine close to intestines lymph, they must first combine intestines lymph lipoprotein, and the lipoprotein response lipid is inhaled Receive and the assembling in absorptive cell,intestinal (enterocyst).And the combination of these lipoprotein then promotes drug transport to enter lymph, because Their size hinders the convenient diffusion of the blood vessel endothelium of the liner capillary across consumption small intestine.Conversely, these big colloids Structure enters lymphatic capillaries, because lymphatic endothelia significantly has more permeability than blood vessel endothelium.Historically, with height The medicine of lymphatic transport has highly lipophilic property, to promote physical bond (generally, but not exclusively, the log D with lipoprotein> 5, and the solubility in LCT>50mg/g).Therefore, the highly lipophilic property analog of medicine is envisioned for promoting A kind of mode of lymph drug transport.However, the chemical modification of parent drug may cause the action intensity to reduce, and in many In situation, lipophilic dramatically increasing is associated with toxicity increase.
The compound of lipophilicity prodrug forms provides a kind of lipoprotein of the lipophilicity sum for being temporarily increased medical compounds The mode of affinity (thus increasing lympha targeted).Transported by lymphatic system, prodrug finally reverts to parent drug, so as to It is active on its target site.
There is the research that several simple aliphatic esters for detecting medicine are used as the potential of the prodrug for orienting lymph.Undecanoic acid testis Ketone provides the example of a compound using the list marketing of the method.After oral, testosterone is several in its first passage liver All it is metabolized completely, final result is that it has minimum bioavilability.The undecylate of testosterone makes the quilt of small scale The dosage of absorption is redirected and enters lymphatic system, is thus avoided liver first-pass metabolism and is increased the oral bioavailability of testosterone Degree.However, this method is still very poorly efficient, and think the bioavilability of testosterone after the oral undecylate< 5%.
Another mechanism for promoting the transfer of lymph medicine is to use prodrug, and the prodrug is combined into the suction with dietary lipids Receive, transport the intrinsic pathway related to disposal.One example of the dietary lipids as prodrug is triglycerides.Medicine-fat The example of matter conjugate has been recorded in a large amount of first publications, wherein parent drug comprising available hydroxy-acid group and (Paris, G.Y. et al., J.Med.Chem.1979,22, (6), 683-687 directly are conjugated with glyceride skeleton；Garzon Aburbeh, A. et al., J.Med.Chem.1983,26, (8), 1200-1203；Deverre, J.R.；Et al., J.Pharm.Pharmacol.1989,41, (3), 191-193；Mergen, F. et al., J.Pharm.Pharmacol.1991, 43, (11), 815-816；Garzon Aburbeh, A. et al., J.Med.Chem.1986,29, (5), 687-69；And Han, Et al. S. J Control.Release 2014,177,1-10).
In other examples, short linker has been used for promoting medicine-triglycerides to be conjugated, wherein medicine is without available Carboxylic acid (Scriba, G.K.E., Arch.Pharm. (Weinheim).1995,328, (3), 271-276；And Scriba, G.K.E. et al., J.Pharm.Pharmacol.1995,47, (11), 945-948).These drug-to-lipid conjugates use amber Amber acid promotes to be conjugated with available hydroxy functional group.However, document instructs this structure at all useless, for example, Scriba is examined Looked into the extracorporeal hydrolysis of testosterone-butanedioic acid-glyceride lipid conjugates, and draw a conclusion " in this research by chemical hydrolysis, The esterase catalyzed hydrolysis of blood plasma and lipase mediation hydrolysis testosterone is only extremely lentamente discharged from prodrug ... therefore, testosterone is sewed Compound looks like the poor prodrug of delivering steroids.”
Other documents used ehter bond be connected with glyceride and ester bond be connected with medicine (Sugihara, J. et al., J.Pharmacobiodyn.1988,11, (5), 369-376；And Sugihara, J. et al., J.Pharmacobiodyn.1988,11, (8), 555-562).The author of these papers is explicitly described, glycerine and n-alkyl chain Between ehter bond and the ester bond between n-alkyl chain and medicine it is seemingly required for the chemical modification of medicine.However, this hair Bright inventor has found that ehter bond is actually reactive, it is impossible to realize significant lymphatic transport.
Therefore, there is demand for researching and developing new lipid-drug active agent conjugates, the conjugate is conducive to medicine to live Property agent be stably transported to intestines lymph and be easy to reply for parent active agent so as to effective.
Summary of the invention
It has been found that it is resulting fat pharmaceutically active agents is connected to triglycerides unit using some " linkers " Matter-pharmaceutically active agents conjugate provides optimal pharmacokinetic properties.
Therefore, on the one hand, the compound of offer formula (I) of the present invention, or its pharmaceutically acceptable salt：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, One or more carbon atoms in alkenyl or alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Aromatics Or aliphatic heterocyclic group is substituted, condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
Represent the residue of pharmaceutically active agents；
- L- be-X '-or-X ' C (O)-；
X ' is O, S, N, N (R4) or S (O)2NH；
Singly-bound is represented, now X ' is O, S, N (R4) or S (O)2NH；Or
Two single keys are represented, now X ' is N；
- Z- is-C (O)-or-C (O) R3-, now-L- be-X '-；Or
- Z- does not exist, now-L- be-X ' C (O)-；
R3It is suicidal group；And
R4It is H or C1-C4Alkyl.
On the other hand, the compound of offer formula (I) of the present invention, it is expressed as formula (II)：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, One or more carbon atoms in alkenyl or alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Aromatics Or aliphatic heterocyclic group is substituted, condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
Represent the residue of pharmaceutically active agents；
- L- be-X '-or-X ' C (O)-；
X ' is O, S or N (R4)；
R4It is H or C1-C4Alkyl；And
- Z- be-C (O)-, now-L- be-X '-；Or
- Z- does not exist, now-L- be-X ' C (O)-；Or
Its pharmaceutically acceptable salt.
On the other hand, the compound of offer formula (I) of the present invention, it is expressed as formula (III)：
Wherein
R1、R2、-X-、With-Z- as defined to formula (I) or formula (II)；
R5And R6It each is selected from hydrogen and C1-C4Alkyl；And
N is 1 to 18；Or
Its pharmaceutically acceptable salt.
On the other hand, the compound of offer formula (I) of the present invention, it is expressed as formula (IV)：
Wherein R1、R2With X as defined to formula (I)；
R5And R6It each is selected from hydrogen and C1-C4Alkyl；
- Z- is-C (O)-or-C (O) R3-；
R3It is suicidal group；And
N is 1 to 18；Or
Its pharmaceutically acceptable salt.
On the other hand, the compound of offer formula (I) of the present invention, it is expressed as formula (V)：
Wherein R1、R2、X、R5、R6With n as defined to formula (IV)；And
- Z- be-C (O)-；Or
Its pharmaceutically acceptable salt.
On the other hand, the present invention provides treatment or prevents the side that wherein increased testosterone levels are beneficial disease or obstacle Method, its compound for including the formula (IV) that therapeutically effective amount is applied to subject in need.
On the other hand, the compound of offer formula (IV) of the present invention is being prepared for treating or preventing wherein increased testosterone water It is flat be beneficial disease or obstacle medicament in purposes.
On the other hand, the compound of offer formula (IV) of the present invention, it is used to treating or preventing wherein increased testosterone levels It is beneficial disease or obstacle.
On the other hand, a kind of method that the present invention provides lymphatic transport for promoting pharmaceutically active agents and systematicness release, its Including making the pharmaceutically active agents be conjugated with the prodrug residue or its pharmaceutically acceptable salt of formula (VI)：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, One or more carbon atoms in alkenyl or alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Aromatics Or aliphatic heterocyclic group is substituted, condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
- Z- be-C (O)-,-C (O) R3- or-CH2-；
R3It is suicidal group；And
Represent the point that linker is conjugated with the pharmaceutically active agents.
To those skilled in the art, combine institute with embodiment and claims reading retouch in detail as follows When stating, the aspects of the invention and other side will be more obvious.
Brief Description Of Drawings
Fig. 1：The mesenterium anaesthetized after intraduodenal infusion testosterone undecanoate (TU) and compound 10,11,14 and 41 drenches The accumulation lymphatic transport (% of institute's application dosage) of testosterone related derivatives total in the female sd inbred rats of hand shaft intubation and time The diagram of relation.
Fig. 2：The male SD of the mesenteric lymph cannula anaesthetized after intraduodenal infusion MPA and compound 30 to 35 is big The figure of the accumulation lymphatic transport (% of institute's application dosage) of total compound comprising Mycophenolic Acid (MPA) and time relationship in mouse Show.
Fig. 3：The male SD of the mesenteric lymph cannula anaesthetized after intraduodenal infusion MPA and compound 31 and 40 is big The figure of the accumulation lymphatic transport (% of institute's application dosage) of total compound comprising Mycophenolic Acid (MPA) and time relationship in mouse Show.
Fig. 4：The mesenteric lymph duct anaesthetized after intraduodenal infusion testosterone undecanoate (TU) and compound 10,16 and 18 The accumulation lymphatic transport (% of institute's application dosage) and time relationship of testosterone related derivatives total in the female sd inbred rats of intubation Diagram.
Fig. 5：The mesenteric lymph anaesthetized after intraduodenal infusion MPA and compound 31,32,34,36,37,38 and 39 Accumulation lymphatic transport (institute's application dosage of total compound comprising Mycophenolic Acid (MPA) in the male SD rat of cannula %) with the diagram of time relationship.
Fig. 6：The mesenteric lymph duct anaesthetized after intraduodenal infusion MPA and compound 30,32,42,43,44 and 45 is inserted In the male SD rat of pipe the accumulation lymphatic transport (% of institute's application dosage) of total compound comprising Mycophenolic Acid (MPA) with The diagram of time relationship.
In the male SD rat of the mesenteric lymph cannula anaesthetized after Fig. 7 intraduodenal infusions MET and compound 3 The accumulation lymphatic transport (% of institute's application dosage) of total metoprolol (MET) related derivatives and the diagram of time relationship.
In the male SD rat of the mesenteric lymph cannula anaesthetized after Fig. 8 intraduodenal infusions ATV and compound 9 The accumulation lymphatic transport (% of institute's application dosage) of total Atorvastatin (ATV) related derivatives and the diagram of time relationship.
In the male SD rat of the mesenteric lymph cannula anaesthetized after Fig. 9 intraduodenal infusions ASP and compound 8 The accumulation lymphatic transport (% of institute's application dosage) of total aspirin (ASP) related derivatives and the diagram of time relationship.
The male SD of the mesenteric lymph cannula anaesthetized after Figure 10 intraduodenal infusions SER and compound 1,6 and 7 The figure of the accumulation lymphatic transport (% of institute's application dosage) of total Sertraline (SER) related derivatives and time relationship in rat Show.
It is total in the male SD rat of the mesenteric lymph cannula anaesthetized after Figure 11 intraduodenal infusions compound 5 The accumulation lymphatic transport (% of institute's application dosage) of celecoxib related derivatives and the diagram of time relationship.
Figure 12：Oral gavage testosterone undecanoate (TU) and compound 10,11,13,14 and 40 to conscious arteria carotis are inserted The female sd inbred rats post dose of pipe normalizes the diagram of testosterone PC.
Figure 13：Oral gavage testosterone undecanoate (TU) (in the form of commercial product Testocaps) and compound 13 are to feeding The female greyhound of food state or oral gavage compound 13 to the greyhound post dose of fasting state normalize testosterone PC Diagram.
Figure 14：Oral gavage testosterone undecanoate (TU) and compound 10,13,16,18 and 19 to conscious arteria carotis are inserted The female sd inbred rats post dose of pipe normalizes the diagram of testosterone PC.
Figure 15：Oral gavage testosterone undecanoate (TU) and compound 11,13,18,19,22,25,26 and 27 are to conscious The female sd inbred rats post dose of arteria carotis intubation normalizes the diagram of testosterone PC.
Figure 16：Oral gavage testosterone undecanoate (TU) and compound 11,18,21 and 23 are to conscious arteria carotis intubation Female sd inbred rats post dose normalizes the diagram of testosterone PC.
Figure 17：Oral gavage testosterone undecanoate (TU) and compound 10,18,28 and 29 are to conscious arteria carotis intubation Female sd inbred rats post dose normalizes the diagram of testosterone PC.
Figure 18：Ah method after oral gavage alfaxalone or compound 2 to the male SD rat of conscious arteria carotis intubation The diagram of salon (ALP) PC.
Figure 19：The monoglyceride form of compound 10,13,16 and compound 18 is big cowardly with fresh collection in vitro Juice and pancreatic juice (for compound 10 and 18) or porcine pancreatic lipase (for compound 13 and 16) stabilization together in incubation period The diagram of property characteristic.
Figure 20：The monoglyceride form of compound 11,13,22,25,26 and 27 is warm together with porcine pancreatic lipase in vitro The diagram of the stability characteristic during educating.
Figure 21：The monoglyceride form of compound 11,13,21,23 and 24 is incubated together with porcine pancreatic lipase in vitro During stability characteristic diagram.
Figure 22：The monoglyceride form of compound 10 and 29 is steady in incubation period together with porcine pancreatic lipase in vitro The diagram of qualitative characteristics.
Figure 23：The monoglyceride form of compound 31,32,34,36,37,38 and 39 is big with fresh collection in vitro The diagram of cowardly juice and pancreatic juice stability characteristic together in incubation period.
Figure 24：In the absence of or intraduodenal infusion MPA in the case of there is 0.6mg JZL184 and 9 μ g orlistats With the compound comprising Mycophenolic Acid (MPA) total in the male SD rat of the mesenteric lymph cannula anaesthetized after compound 32 Accumulation lymphatic transport (% of institute's application dosage) and time relationship diagram.
Detailed description of the invention
When prodrug strategies are used for course of drug development to improve pharmacokinetic properties, being generally expected to prodrug can pass through It is parent compound that nonspecific degradation or the bioconversion of enzyme mediation are replied, and then shows bioactive.The present invention is disclosed The compound of the glyceride based on modification, they can promote the lymphatic transport of pharmaceutically active agents and improve the compound It is active pharmaceutical substance to reply.
The unique metabolisming way of dietary lipids, such as triglyceride application (and is eventually arrived at obtaining into lymph Body circulation), its metabolisming way for being totally different from other nutrients (such as protein and carbohydrate).Upon intake, meals By body cavity lipase hydrolysis, each triglycerides molecule discharges a monoglyceride and two aliphatic acid to food triglyceride. The monoglyceride and two aliphatic acid are then absorbed into enterocyte, and they are esterified into triglyceride again there.
The chyle that the triglyceride for synthesizing again is assembled into tripe tallow albumen (mainly chylomicron) and is consequently formed is micro- Grain from enterocyte exocytosis out, and then obtain preferentially enter intestines lymphatic vessel.In lymphatic vessel, the lipid of chylomicron form leads to Cross a series of capillaries, tubercle and delivery pipe discharge, finally the junction of left subclavian vein and jugular vein empty into Enter body circulation.After blood circulation is entered, the triglyceride in chylomicron is preferential and effectively by with lipoprotein lipid high The tissue (such as adipose tissue, liver and potential certain form of tumor tissues) of fat expression of enzymes absorbs.
Expected lipid simulation compound is similar with the esters behavior of natural glycerin three, and is transported before body circulation is reached To lymphatic system and by lymphatic system.In this manner it is achieved that the pharmacokinetics and pharmacodynamic profiles of parent drug activating agent Enhancing can be operable to and enter lymph and lymphoid tissue, improved from there through first-pass metabolism (and potential intestines flow out) is avoided Oral administration biaavailability.Lipid simulation compound can also promote in drug targeting to lymph, lymph node and lymphoid tissue Position and lipid high are using the position with lipoprotein lipase expression, such as adipose tissue and some tumours.
The lipidization prodrug of parent drug is readily converted into stomach and intestine (GI) road is reduced after being transported by body circulation Free drug concentration, this can be in reduction gastrointestinal irritation, taste masking, promotion medicine in terms of solubilising in intestines bile salt micelle Passive membrane permeability aspect (by increasing lipophilicity) of (being attributed to the similarity with endogenous monoglyceride class) and raising carries For benefit.Lipidization prodrug is also improved comprising single lipid or lipid and surfactant and/or the mixture of cosolvent Lipid carrier in solubility, and this is done so that can be with more than being probably feasible dosage molten with medicine to parent drug Liquid is applied.
The present inventor is it has surprisingly been found that pharmaceutically active agents to be connected to the medicine-glycerine of glycerine ester units The part of ester conjugate can be modified, and to improve stability of the medicine-glyceride conjugates in GI roads, promotion is transported to intestines Lymph, and finally promote pharmaceutically active agents to be discharged from pharmaceutically active agents-glycerine ester prodrugs.Therefore, medicine is lived by changing Property agent be connected to " linker " of glycerine ester units, can realize that optimal pharmacokinetics is special for resulting compound Property.
In this manual, a large amount of terms well known to the skilled person are applied.Even so, still in order to Understand purpose, define a large amount of terms.
In this manual, unless otherwise defined, otherwise term " optionally substituted " refer to group can further by One or more substituent groups, it is also possible to not by these substituent groups, the group is selected from hydroxyl, alkyl, alkoxy, alkoxy Carbonyl, alkenyl, alkenyloxy group, alkynyl, alkynyloxy group, amino, aminoacyl, thio, aryl alkyl, alkoxy aryl, aryl, fragrant oxygen Base, acyl amino, carboxyl, cyano group, halogen, nitro, sulfo group, phosphono, phosphoryl amino, phosphino-, heteroaryl, heteroaryloxy, Heterocyclic radical, heterocyclic oxy group, trihalomethyl group, pentafluoroethyl group, trifluoromethoxy, difluoro-methoxy, trifluoromethylthio, trifluoro-ethylene Base, one-and di-alkyl amino, one-and two-(substituted alkyl) amino, one-and two-arylamino, one-and two-heteroaryl The amine of amino, one-and two-heterocyclic radical, amino and the asymmetric di-substituted with different substituents, the substitution base is selected from Alkyl, aryl, heteroaryl and heterocyclic radical.
As used in this application, exclusive use or the term " alkyl " used in compound word represent straight chain or branch Alkyl group.Prefix such as " C2-C20" for representing the carbon number in alkyl (being in this case 2-20).Straight chain and The example of branched alkyl include methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, tert-butyl, n-pentyl, hexyl, Heptyl, 5- methylheptyls, 5- methylhexyls, octyl group, nonyl, decyl, hendecyl, dodecyl and docosyl (C22)。
As used in this application, exclusive use or the term " alkenyl " used in compound word are represented comprising at least One straight or branched hydrocarbon residue of carbon-to-carbon double bond, including olefines as defined above is single-, two- or how unsaturated alkane Base.Preferably, alkenyl is straight-chain alkenyl.Prefix such as " C2-C20" for representing the carbon number in alkenyl (in this case It it is 2-20).The example of alkenyl include vinyl, pi-allyl, 1- methyl ethylenes, cyclobutenyl, iso- cyclobutenyl, 3- methyl- 2- cyclobutenyls, 1- pentenyls, 1- hexenyls, 3- hexenyls, 1- heptenyls, 3- heptenyls, 1- octenyls, 1- nonenyls, 2- nonyls Alkenyl, 3- nonenyls, 1- decene base, 3- decene base, 1,3- butadienyls, 1,4- pentadienyls, 1,3- hexadienyls, 1,4- oneself Dialkylene and 5- docosene bases (C22)。
As used in this application, exclusive use or the term " alkynyl " used in compound word are represented comprising at least One straight or branched hydrocarbon residue of carbon-to-carbon triple bond, including olefines as defined above is single-, two- or how unsaturated alkane Base.Preferably, alkynyl is straight-chain alkynyl.Prefix such as " C2-C20" for representing the carbon number in alkynyl (in this case It it is 2-20).
As used in this application, exclusive use or the term such as " heterocycle " or " heterocycle that are used in compound word Base " represents saturation, part insatiable hunger and/or completely unsaturated monocyclic, bicyclic or fused polycyclic ring system, and it includes at least one and is selected from The hetero atom of nitrogen, sulphur and oxygen.Prefix such as " C5-C8" for representing the carbon number in the group annulus (in such case In be 5-8).The example of suitable heterocyclic substituent includes, but are not limited to pyrroles, furans, benzofuran, benzothiazole, miaow Azoles, benzimidazole, imidazoline, pyrazoles, pyrazoline, triazole,Azoles,It is oxazoline, differentIt is azoles, differentOxazoline, furazan,Two Azoles, piperidines, pyridine, pyrimidine, pyridazine and pyrazine, each of which further can be taken by 1-3 substitution base.
As used in this application, term such as " aryl " or " aromatic cyclic group " represents sewing for any monokaryon or multinuclear The residue of aromatic hydrocarbyl ring system closing or condensing.Prefix such as " C5-C8" for representing the carbon number in aryl annulus (being in this case 5-8).The example of aryl includes that phenyl (monokaryon), naphthyl (condensing multinuclear), xenyl are (conjugated Multinuclear) and tetralyl (multinuclear for condensing).
As used in this application, term " linker " is represented for the compound of formula (I) described herein The compound part of from " X " to " L ", it makes pharmaceutically active agents be connected to glycerine ester units.
As used in this application, term " suicidal group " defines a kind of chemical part, and it is formed with linker The key of easy fracture, forms stable key, wherein becoming not when linker is cracked with the key of pharmaceutically active agents with pharmaceutically active agents Stabilization.The example of suicidal group include, but are not limited to the suicidal group of acetal, to hydroxybenzyl carbonyl self The group of destruction, suicidal group and the trimethyl suicidal group of lock for overturning ester.Many other suitable self The group of destruction is well known in the art, for example Blencowe et al., Polym.Chem.2011,2,773-790 and Kratz et al. Chem Med Chem.2008, described in 3,20-53.
As used in this application, term " pharmaceutically active agents " represents arbitrary pharmaceutically active substance or imaging (radiography) Agent, it will benefit from being transported by intestines lymphatic system, such as avoiding first-pass metabolism or for the targeted delivery in lymphatic system.
The example of suitable pharmaceutically active agents include, but are not limited to testosterone, Mycophenolic Acid, estrogen (estrogen), morphine, Metoprolol, Raloxifene, alfaxalone, statins for example Atorvastatin, pentazocine, Propranolol, L-DOPA, Buprenorphine, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, pentazocine, ISDN, three Glycerin trinitrate, oxprenolol, labetalol, Verapamil, salbutamol, epithioandrostanol, melphalan, Lovastatin, non-steroid AID (NSAIDS, such as aspirin, brufen, naproxen), cox 2 inhibitor (such as celecoxib, Rofe former times Cloth), corticosteroid anti-inflammatory agent (such as prednisolone, metacortandracin, dexamethasone), antimalarial (such as HCQ), ring phosphinylidyne Amine, nitrosoureas, platinum, methotrexate (MTX), imuran, mercaptopurine, fluorouracil, actinomycin D, anthracycline are (such as soft red Mycin), mitomycin C, bleomycin, mithramycin, act on suppression and exempt from medicine (such as cyclosporine, tacrolimus, the west of albumen Luo Mosi), SASP, leflunomide, mycophenolate, opioid, FTY720, myriocin, benzenebutanoic acid nitrogen Mustard, Doxorubicin, nelarabine, cortisone, dexamethasone, metacortandracin, Pralatrexate, vincaleukoblastinum, bortezomib, thiotepa, how Draw shore, daunorubicin hydrochloride, clofarabine, cytarabine, Dasatinib, imatinib mesylate, hydrochloric acid Ponatinib, sulfuric acid Vincristine, bendamustine hydrochloride, fludarabine phosphate, SKI-606, AMN107, U.S. amber his pungent, Anastrozole, card training He is shore, Letrozole, taxol, gemcitabine, fulvestrant, TAM, Lapatinib, Toremifene, Ipsapirone, Ai Li It is Bu Lin, albendazole, ivermectin, diethylcarbamazine, albendazole, Doxycycline, closantel, MVC, T-20, de- Oxygen thymidine, Zidovudine, stavudine, Didanosine, zalcitabine, Abacavir, Lamivudine, grace it is bent he Shore, tenofovir, NVP, Delavirdine, efavirenz, rilpivirine, drawing are for drawing Wei, Ai Weileiwei, Lopinavir, indenes That Wei of ground, Nai Feinawei, APV, Ritonavir, ACV and pharmaceutical activity peptides.
The example of suitable preparation includes, but not limited to fluorogen, for example for fluorescence microscopy or be used for The optical imaging probe of the wherein fluorogen of in-vivo imaging Alexa Fluor series with emission spectrum in infra-red range； Can be used for the gamma emitter of positron emission tomography (PET), such as FDG or chelating agent, to chelate Magnetic resonance imaging probe, such as gadolinium or iron.
For the compound of formula (I), when X ' is-O- or-S-, groupIt isI.e.Table Show singly-bound.However, when X ' is N,Two single keys are represented, i.e., is not double bond, they make nitrogen-atoms be connected to composition medicine The single atom of two of the part of thing activating agent.For exemplary compound, compound 1,6 and 7, wherein medicine are lived Property agent is the Sertraline with following chemical constitution：
Two single keys are the key and the key from nitrogen-atoms to methyl of 2,3,4- naphthane parts from nitrogen-atoms to 1, this When linker be bonded to the secondary nitrogen-atoms of Sertraline.For example, when pharmaceutically active agents are the tenofovirs with following structure：
Two single keys are the key from nitrogen-atoms to purine moiety and the key from nitrogen-atoms to hydrogen atom, now linker It is bonded to available primary amine.Similarly, if pharmaceutically active agents are the labetalols with following structure：
And linker is bonded to available amide group, then two single keys are from nitrogen-atoms to carboxyl carbon atom Key and the key from nitrogen-atoms to hydrogen atom.Compound for formula (I) is referred toIt is not intended to imply that nitrogen-atoms passes through double bond key It is bonded to pharmaceutically active agents.
It is involved " equivalent to straight chain C to avoid any doubt20The length of alkyl " refers to that the carbon of 20 odd number bondings is former The length that son launches in theory.
In some preferred embodiments of the invention, on leading to formula (I), one or more being defined as below are applicable：
a)R1And R2Independently represent H or C2-C28The residue of aliphatic acid.
b)R1Represent H, and R2Represent C2-C28The residue of aliphatic acid.
c)R2Represent H, and R1Represent C2-C28The residue of aliphatic acid.
d)R1And R2Each represent palmitic acid.
E)-X- is-O-.
F)-X- is-NH-.
G)-X- is-S-.
H)-Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkane One or more of carbon atom on base, alkenyl or alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8 Aromatics or aliphatic heterocyclic group are substituted, and condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl.
I)-Y- represents-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, they are optionally replaced by alkyl.
J)-Y- represents-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, they are optionally replaced by methyl.
K)-Z- is C (O) R3-, now-L- is-X'-, and R3It is suicidal group.
l)R3Suicidal group, its be selected from acetal, trimethyl lock, to hydroxybenzyl carbonyl or upset ester from The group that I destroys.
M)-Z- be-C (O)-, now-L- is-X'-.
N) X' is O.
O) X' is S.
P) X' is N.
Q) X' is N (R4)。
r)R4It is H.
s)R4It is C1-C4Alkyl.
t)R4It is methyl.
In a preferred embodiment ,-Z- be-C (O)-, now-L- is-X'-.
Therefore, in another embodiment, the compound of offer formula (I) of the present invention, it is expressed as formula (II)：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, One or more of carbon atom on alkenyl or alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Virtue Race or aliphatic heterocyclic group are substituted, and condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
Represent the residue of pharmaceutically active agents；
- L- be-X'- or-X'C (O)-；
- Z- be-C (O)-, now-L- is-X'-；Or
- Z- does not exist, now-L- be-X'C (O)-；And
X ' is selected from O, S and NR4；And
R4It is H or C1-C4Alkyl；Or
Its pharmaceutically acceptable salt.
In another embodiment, the compound of offer formula (I) of the present invention, it is expressed as formula (III)：
Wherein
R1、R2、-X-With-Z- as defined to formula (I)；
R5And R6It each is selected from hydrogen and C1-C4Alkyl；And
N is 1 to 18；Or
Its pharmaceutically acceptable salt.
In another embodiment, the compound of formula (III) is selected from those compounds listed in table 1.
The compound of the following formula of table 1.：
1TML=trimethyls lock suicidal group；2PHB=is to the suicidal group of hydroxybenzyl carbonyl；3ASI= The suicidal group of acetal.
In one embodiment, the pharmaceutically active agents are testosterones or derivatives thereof or the like.Testosterone alternative medicine (TRT) it is usually used in the patient with hypogonadism (being characterised by the obstacle of abnormal low level of serum testosterone), so that its Level of serum testosterone recovers to normal range (NR) and thus alleviates many symptoms of hypogonadism, such as emotionally disturbed, property Dysfunction etc..
Therefore, in one embodiment, the compound of offer formula (I) of the present invention, it is expressed as formula (IV)：
Wherein R1、R2With X as defined to formula (I)；
R5And R6It each is selected from hydrogen and C1-C4Alkyl；
- Z- is-C (O)-or-C (O) R3-；
R3It is suicidal group；And
N is 1 to 18；Or
Its pharmaceutically acceptable salt.
In another embodiment, the compound of formula (IV) is selected from those compounds listed in table 2.
The compound of the formula of table 2. (IV)：
1The suicidal group of ASI=acetals；2TML=trimethyls lock suicidal group；3PHB=is to hydroxyl benzyl The suicidal group of base carbonyl；4FSI=overturns the suicidal group of ester.
In another embodiment, it is beneficial disease that the present invention provides treatment or prevents wherein increased testosterone levels Or the method for obstacle, its compound for including the formula (IV) that therapeutically effective amount is applied to subject in need.
In another embodiment, the compound of offer formula (IV) of the present invention is being prepared for treating or preventing wherein to increase Plus testosterone levels be purposes in the medicament of beneficial disease or obstacle.
In another embodiment, the compound of offer formula (IV) of the present invention, it is used to treat or prevents wherein to increase Testosterone levels be beneficial disease or obstacle.
Wherein described increased testosterone levels are probably that beneficial disease and obstacle include, but are not limited to hypogonadism Disease, because anaemia caused by marrow failure, because anaemia caused by kidney failure, chronic respiratory failure, chronic heart failure, steroids according to Rely property autoimmune disease, AIDS consumption, HAE or nettle rash, advanced breast cancer or menopause.
In another embodiment, the pharmaceutically active agents are Mycophenolic Acid (MPA).MPA to lymphocyte in it is fast Purine route of synthesis works and is the wide variety of immunodepressant for treating autoimmune disease and organ-graft refection.
Therefore, in another embodiment, the compound of offer formula (I) of the present invention is or, it is expressed as formula (VII)：
Wherein R1、R2, X and X' is to formula (I) as defined；
R5And R6It each is selected from hydrogen and C1-C4Alkyl；And
N is 1 to 18；Or
Its pharmaceutically acceptable salt.
In another embodiment, the compound of formula (VII) is selected from those compounds listed in table 3.
The compound of the formula of table 3. (VII)：
In another embodiment, the present invention provides the side for the treatment of or preventing autoimmune disease and organ-graft refection Method, its compound for including the formula (VII) that therapeutically effective amount is applied to subject in need.
In another embodiment, the compound of offer formula (VII) of the present invention is being prepared for treating or preventing itself Purposes in the medicament of immunological diseases and organ-graft refection.
In another embodiment, the compound of offer formula (VII) of the present invention, it is used to treating or preventing autoimmunity Disease and organ-graft refection.
In another embodiment, the present invention provides the side for promoting pharmaceutically active agents lymphatic transport and systematicness release Method, it includes making the prodrug residue or its pharmaceutically acceptable salt of formula (VI) to be conjugated to the medical compounds：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, One or more of carbon atom on alkenyl or alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Virtue Race or aliphatic heterocyclic group are substituted, and condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
- Z- be-C (O)-,-C (O) R3- or-CH2-；
R3It is suicidal group；And
Point is represented, wherein linker is conjugated to pharmaceutically active agents.
In one embodiment, the Y and Z to compound as defined above are selected, to be conducive to medicine to live Property agent is stably transported to intestines lymph.In another embodiment, Y and Z are selected, to be conducive to pharmaceutically active agents to exist Lymph, lymphocyte, lymphoid tissue, the tissue with higher fatty acid enzymatic activity such as adipose tissue, certain cancers, liver or body are followed Discharged in ring.In another embodiment, Y and Z are selected, be conducive to pharmaceutically active agents be transported to intestines lymph and Be conducive to pharmaceutically active agents lymph, lymphocyte, lymphoid tissue, such as adipose tissue of the tissue with higher fatty acid enzymatic activity, Discharged in certain cancers, liver or body circulation.
Compound of the invention be used for stably by pharmaceutically active agents be transported to intestines lymph and lymph, lymphocyte, Medicine is discharged in lymphoid tissue, the tissue with higher fatty acid enzymatic activity such as adipose tissue, certain cancers, liver or body circulation to live Property agent.Compound of the invention is particularly used for transporting and discharging the pharmaceutically active agents for having benefited from avoiding first-pass metabolism, for example, exhibition Compound more than 50% first-pass metabolism is shown.In one embodiment, it is contemplated that the pharmaceutically active agents show and are more than 60% first-pass metabolism.In another embodiment, the pharmaceutically active agents show the first-pass metabolism more than 70%.Another In one embodiment, the pharmaceutically active agents show the first-pass metabolism more than 80%.In another embodiment, it is described Pharmaceutically active agents show the first-pass metabolism more than 90%.
Can have benefited from stably being transported to intestines lymph and lymph, lymphocyte, lymphoid tissue, with higher fatty acid enzyme The pharmaceutically active agents of tissue such as adipose tissue, certain cancers, liver or the body circulation of activity include, but are not limited to testosterone, wheat Examine phenolic acid, estrogen (estrogen), morphine, metoprolol, Raloxifene, alfaxalone, statins such as atropic and cut down him Spit of fland, pentazocine, Propranolol, L-DOPA, buprenorphine, midazolam, lidocaine, chlorpromazine, amitriptyline, first is gone to replace Woods, pentazocine, ISDN, trinitin, oxprenolol, labetalol, Verapamil, salbutamol, ring Sulphur hero alcohol, melphalan, Lovastatin and pharmaceutical activity peptides.
Compound of the invention is additionally operable to Targeting delivery of the pharmaceutically active agents in lymphatic system, for example lymph, In lymphocyte and lymphoid tissue and the tissue with higher fatty acid enzymatic activity such as adipose tissue, certain cancers or liver.
The pharmaceutically active agents that the Targeting delivery in lymphatic system or adipose tissue can be had benefited from include, but are not limited to non-steroid AID (NSAIDS, such as aspirin, brufen, naproxen), cox 2 inhibitor (such as celecoxib), cortex class Nonsteroidal antiinflammatory medicine (such as prednisolone, dexamethasone), antimalarial (such as HCQ), endoxan, PPAR activators are (for example Fibrates), nitrosoureas, platinum, methotrexate (MTX), imuran, mercaptopurine, fluorouracil, actinomycin D, anthracycline, mitogen Mycin C, bleomycin, mithramycin, act on suppression and exempt from medicine (such as cyclosporine, tacrolimus, sirolimus), the willow of albumen Nitrogen sulphur pyridine, leflunomide, mycophenolate, opioid, FTY720, myriocin, Chlorambucil, how soft ratio Star, nelarabine, cortisone, dexamethasone, metacortandracin, Pralatrexate, vincaleukoblastinum, bortezomib, thiotepa, nelarabine, hydrochloric acid Daunorubicin, clofarabine, cytarabine, Dasatinib, imatinib mesylate, hydrochloric acid Ponatinib, vincristine sulphate, Bendamustine hydrochloride, fludarabine phosphate, SKI-606, AMN107, U.S. amber his pungent, Anastrozole, capecitabine, come bent Azoles, taxol, gemcitabine, fulvestrant, TAM, Lapatinib, Toremifene, Ipsapirone, Ai Libulin, acetysalicylic acid phenobarbital Up to azoles, ivermectin, diethylcarbamazine, Doxycycline, closantel, MVC, T-20, deoxythymidine, neat Many husbands are fixed, stavudine, Didanosine, zalcitabine, Abacavir, Lamivudine, emtricitabine, tenofovir, Nai Weila Flat, Delavirdine, efavirenz, rilpivirine, drawing are for drawing Wei, Ai Weileiwei, Lopinavir, indinavir, Nai Feinawei, ammonia Pune's Wei, Ritonavir, ACV and immunodepressant such as Mycophenolic Acid, cyclosporin, tacrolimus and sirolimus.
Used as general strategy, compound of the invention can be synthesized by one of following path.
The synthesis of the compound of the unsubstituted alkyl-connection of the invention of scheme 1., wherein L is X ', and X ' is O
As shown in scheme 1, can be by making acid-triglycerides IV with the pharmaceutically active agents (A-OH) comprising alcohol in standard Ester-key reacts under the conditions of being formed, and compound of the invention is prepared, wherein-Y- is unsubstituted alkyl.In most of situation In, can by the presence of pyridine with reason acid anhydrides I (n=1) or diacid chloride II (n at 1,3- DGs III>1) (deriving from corresponding dicarboxylic acids) obtains the acid-triglycerides IV.
In order to synthesize compound, wherein-Y- is the alkyl of alpha-substituted or β-substitution, acid anhydrides I or diacid chloride II passes through scheme 1 Described in path change into acid-triglycerides IV and atypically feasible because raw material is asymmetric.Therefore, via side The synthesis of case 1 will result in the acid-triglyceride products of mixing.In such cases, linker unit can be by more simple Single material construction, and then merge with DG III in suitable point in sequence, finally give acid-triglycerides IV。
The synthesis of the compound of the alpha-substituted of the invention of scheme 2.
In order to synthesize comprising alpha-alkyl substitution alkyl linker compound, can by the aldehyde derived from alcohol VI with it is steady Fixed is interiorWittig reaction between salt VII assembles the required carbon skeleton for interval base, obtains alpha-alkyl-α, β-insatiable hunger The ester VIII of sum.After ester hydrolysis release free acid IX, it is coupled at the standard conditions with DG III, obtains glycerine Three ester X.One step hydrogenation-hydrogenolysis obtains saturated alcohols XI, is oxidized first by PCC, obtains aldehyde XII, then further exists Aoxidized under the conditions of Pinnick, obtain the acid-triglycerides IV of desired alpha-substituted.
The synthesis of the compound of the β-substitution of the invention of scheme 3.
In order to synthesize comprising β-compound of alkyl-substituted alkyl linker, the method summarized in such scheme 1 can be with For the wherein particular case of n=1, because β-substitution base maintains the symmetry in diacid chloride II.Such scheme 3 is provided for closing Into the method for the compound comprising β-alkyl substituent, in this case, wherein n>1.Finally, made using highly basic such as n-BuLi TMS acetylene deprotonations, are then added as the alkyl bromide XIII of electrophilic body, result in silicyl alkynes XIV.Removing first silicon After alkylation, PdIIAnd CuIThe alkynes XV of mediation is included with the Sonogashira cross couplings of enol triflate XVI The eneyne XVII of required β-alkyl substituent.The catalytic hydrogenation of eneyne XVII obtains Beta-methyl-ω-hydroxy ester XVIII, and it can be with TBDPS ether XIX are converted to, the preparation for importing glyceride functional group.Then by (the 2M KOH under alkalescence condition of pressurizeing EtOH solution, at 60 DEG C) hydrolysis ester XIX carries out, and the sour XX that obtains and DG III is carried out standard idol Close, obtain triglycerides XXI.Then obtain hydroxyl triglycerides XI using TBAF removal monosilane bases, can according to scheme 2 in The similar mode of summary converts it into target acid-triglycerides IV.
The synthesis of the compound of scheme 4., wherein L be-X ' C (O)-, and X ' is O or S
If pharmaceutically active agents carry the hydroxy-acid group that can be conjugated and to form the compounds of this invention, the compound generally may be used Prepared with according to scheme 4.In order to generate ester bond between glyceride and desired linker, make ω-halogenated carboxylic acid XXII and 1, 3- DGs III is coupled in the presence of standard coupling conditions, obtains ω-halo triglyceride XXIII.Comprising carboxylic acid The conjugated of pharmaceutically active agents can then be carried out by replacing halogen leaving group with suitable carboxylate nucleophile, obtain this hair Bright compounds X XIV.In this case, wherein halogenated carboxylic acid XXII is not commercially available, is to expect from the synthesis of simpler precursor 's.For shorter chain (n=2,3), alpha-alkyl or β-alkyl-substituted example or long-chain are (for example：N=12) unsubstituted reality Example, can obtain necessary sour XXII by the open loop of corresponding lactone (referring to embodiment 6, compound a j-am).For long-chain Alpha-alkyl or β-examples of alkyl (n>3), necessary halo triglyceride XXIII can be by the hydroxyl described in such scheme 2 and 3 It is prepared by the ester XI of base glycerol three.
If compound of the invention needs purifying, can for example be recrystallized and chromatographic technique using multiple technologies, wrapped Include high performance liquid chromatography (HPLC) and positive or reverse phase silica gel chromatography.The compound can use nuclear magnetic resonance (NMR) matter Spectrometry and/or other suitable methods are characterized.
It should be appreciated that (such as diastereomeric can be present with one or more stereoisomer form in compound of the invention Isomers).The present invention in the range of it include all these separation (such as Chiral Separation) or combination (including racemic mixing Thing and non-enantiomer mixture) stereoisomer form.
The present invention thus also relates to the substantially pure stereoisomer form of the asymmetric center on amino acid residue Compound, be greater than about 90%de, e.g., from about 95% to 97%de or more than 99%de, and mixture, including outside it Racemic mixture.This kind of diastereoisomer can be prepared by asymmetric syntheses for example with chiral intermediate, or can be with Mixture is split by conventional method, for example, chromatography or applies resolution reagent.
If the compound comprising one or more can protonate or deprotonation functional group (such as in physiological pH Under), then the compound can be prepared and/or separated as pharmaceutically acceptable salt.It should be appreciated that the compound is being specified It can be zwitterionic form under pH.Statement " pharmaceutically acceptable salt " use herein refers to specified compound Salt, the wherein salt is adapted as medicament administration.This kind of salt can be reacted by making acid or alkali respectively with amine or hydroxy-acid group Formed.
Pharmaceutically acceptable acid-addition salts can be prepared by inorganic acid and organic acid.The example of inorganic acid include hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..The example of organic acid include acetic acid, propionic acid, glycolic, pyruvic acid, oxalic acid, malic acid, Malonic acid, butanedioic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, P-methyl benzenesulfonic acid, salicylic acid etc..
Pharmaceutically acceptable base addition salts can be prepared by inorganic base and organic base, corresponding flat derived from inorganic base Weighing apparatus ion includes sodium, potassium, lithium, ammonium, calcium and magnesium salts.Organic base includes the amine of primary, secondary and tertiary amine, substitution including naturally occurring Substituted amine and cyclammonium class, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA), monoethanolamine, 2- diformazan ammonia Base ethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, Hai Baming (hydrabamine), courage Alkali, glycine betaine, ethylenediamine, aminoglucose, N- alkylated glucamines, theobromine, purine, piperazine, piperidines and N-ethylpiperidine.
Acid/base addition salts tend to than corresponding free acid/base form more soluble in aqueous solvent.
Compound of the invention can be crystal formation or be solvate (such as hydrate), and it is expected both belong to this In the range of invention.Term " solvate " is the compound of the varying chemical amount of calculation that solute and solvent are formed.This kind of solvent Should not interfere with the bioactivity of solute.Used as example, solvent can be water, ethanol or acetic acid.Solvation process generally makes this Known to field.
The administration of the compounds of this invention includes that oral and intestines are applied by way of expected.Therefore, the reactive compound can be with lazy Property diluent or assimilable edible carrier prepare, or can be encapsulated in hard-shell capsule or soft shell capsule, or can be with Tablet is compressed into, or meals food can be directly incorporated into.In order to oral medication apply, can by reactive compound with Excipient is blended and can take in tablet, mouth containing or sublingual tablet, tablet, capsule, elixir, suspension, syrup, wafer capsule The form of agent etc. is used.Amount in the useful composition in this kind for the treatment of of reactive compound allows to obtain suitable agent Amount.
The tablet, tablet, pill, capsule etc. can also include it is set forth below go out composition：Adhesive can be added, Such as natural gum, Arabic gum, cornstarch or gelatin；Excipient, such as Dicalcium Phosphate；Disintegrant, such as cornstarch, Ma Ling Sweet potato starch, alginic acid etc.；Lubricant, such as magnesium stearate；And sweetener, such as sucrose, lactose or saccharin, or flavouring, example Such as peppermint, wintergreen or cherry essence.When formulation is capsule, in addition to materials of the above type, it can also be carried comprising liquid Body.Various other materials can be provided as coating agents, can otherwise change the physical form of formulation.For example, worm can be used Glue, sugar or both be coated to tablet, pill or capsule.Syrup or elixir can be comprising reactive compounds, as sweet taste The sucrose of agent, methyl p-hydroxybenzoate and propylparaben, dyestuff and the Flavouring agents such as cherry as preservative Or orange flavor.Certainly, for prepare any materials of arbitrary unit formulation should be pharmacy it is pure and in usage amount it is basic On be nontoxic.Furthermore, it is possible to compound of the invention is mixed into Sustained release preparations and preparation, including can be by active peptide Be delivered to intestines specific region those.
Can also be by stomach or the enteral liquid preparation of esophageal tube.
In one embodiment, by orally applying to promote to be transported to intestines compound of the invention together with food Lymph.
In another embodiment, by compound of the invention together with the preparation with lipid as matrix oral administration, To promote the food with or without common use to be transported to intestines lymph together.
Be well known in the art and can include for the preparation with lipid as matrix of oral delivery, such as it is substantially non- The medium of water, it typically comprises one or more lipid components.Lipid carrier and the lipid formulations for obtaining can be usefully It is as described below according to its total public same feature, classified according to lipid formulations categorizing system (LFCS) (Pouton, C.W., Eur.J.Pharm.Sci.11 (supplementary issue 2), S93-S98,2000；Pouton, C.W., Eur.J.Pharm.Sci.29278-287, 2006)。
Therefore, lipid carrier and the lipid formulations that obtain can comprising oil/lipid and/or surfactant, optionally with Cosolvent.I types preparation includes needing the oil or lipid of digestion, such as mono-, di- and Three-glycerol esters and combinations thereof.II type preparations The SEDDS of water is insoluble in, it is included for the lipid and oil of I type preparations and other water insoluble surfactants.Type III Preparation is the delivery system (SMEDDS) of SEDDS or certainly-microemulsified, and it is included for the lipid and oil of I type preparations and other water The water soluble ingredient (IIIb types) of soluble surfactants and/or cosolvent (IIIa types) or greater proportion.IV type preparations are main Comprising hydrophilic surfactant active and cosolvent (such as PEG, propane diols and carbitol) and for being insoluble in water and Non- lipophilic medicine.Any this kind of lipid formulations (I-IV types) are concerns in the application.
In some embodiments, lipid carrier includes one or more oil or lipid, without other surfactants, auxiliary Cosurfactant or coemulsifier or cosolvent, it is believed that one or more oil of their major oils or lipid composition.In addition In some embodiments, lipid carrier includes one or more oil or lipid and one or more water insoluble surface-active Agent, optionally with one or more cosolvent.In other embodiments, lipid carrier includes one or more oil or fat Matter and one or more water soluble surfactant active, optionally with one or more cosolvent.In some embodiments, lipid Mixture of the carrier comprising oil/lipid, surfactant and cosolvent.In some embodiments, lipid carrier is mainly by one Plant or kinds of surface activating agent/cosurfactant/coemulsifier and/or solvent/co-solvent composition.
The example that can be used for oil of the invention or lipid includes apricot kernel oil, babassu oil, black currant pip oil, Common Borage Oil, Jie's caul-fat, castor oil, coconut oil, cod-liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape-kernel oil, mustard seeds Oil, olive oil, palm-kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, dogfish oil, soybean oil, sunflower Oil, nut oil, wheat-germ oil, avocado oil, oil extracted from rice husks, rilanit special, hydrogenated coconut oil, cotmar, HPO, Triglycerides, three that oil with hydrogenated soybean, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic/capric triglyceride, classification are separate It is glycerol decanoate, tricaproin, tricaprylin, three caprylic/capric glyceride, three caprylic/capric glyceride, three pungent Acid/silicic acid/glyceryl laurate ester, three octanoic acids/silicic acid/glyceryl linoleate, three octanoic acids/silicic acid/tristerin, three bays Acid glyceride, glyceryl monolaurate, Compritol 888 ATO, Masine 35-1, Trilinoleyl glyceride, three oleics Ester, myricinic acid glyceride, glyceryl tristearate glyceryl linoleate, saturated polyglycolysed glyceride, mainly include C8-C12The synthesis medium chain triglyceride of fatty acid chain, mainly include C8-C12The medium chain triglyceride of fatty acid chain, mainly include> C12Triglycerides and its mixture that the LCT of fatty acid chain, the triglycerides of modification, classification are separate.
The example that can be used for monoglyceride of the invention and diglyceride includes thering is the 8-40 fat of carbon atom The one of sour chain-and two esters, including the coconut oil for hydrolyzing is (for exampleMCM), hydrolysis corn oil (for example MaisineTM35-1).In some embodiments, monoglyceride and diglyceride are with the 8-18 fat of carbon chain lengths List-or two-saturated fatty acid esters (such as glycerin monostearate, distearin, single octanoic acid of the glycerine of fat acid chain Glyceride, two glycerol caprylates, Capmul MCM C10 and two glycerol decanoates).
Suitable surfactant for lipid formulations includes C8-C22The propane diols one of aliphatic acid-and two -ester, for example, But be not limited to Sefsol 218, propylene, PGML, its with trade name for example90、PG、FCC sells；Sugar fatty acid esters, for example, but not limiting In palmitic acid sucrose ester, sucrose laurate, stearic acid sucrose ester；Sorbitan fatty acid esters class, such as, but not limited to Sorbitan Laurate, Sorbitan Palmitate, Sorbitan Oleate；Polyoxyethylene water sorbitan fatty acid esters, such as, but not limited to poly- PS20, polysorbate40, polysorbate60 and polysorbate80, polysorbate85；Polyoxyethylene one-with Two-fatty acid ester, includes, but are not limited to Myrj 52 and the oleate of polyoxyethylene 40；C8-C22Aliphatic acid The mixture and C of polyoxyethylene one-and two -ester classes8-C22The glycerine one of aliphatic acid-, two-and three-ester class, its retailer's name of an article For for example44/14、50/13、Polyoxyethylene castor Sesame oil compound, hydrogenates such as, but not limited to Emulsifier EL-35, polyoxyl 40 hydrogenated castor oil and polyoxyethylene 60 Castor oil, its as trade name for exampleEL、 RH40、RH60 sells；Polyoxyethylene alkyl ether, includes, but are not limited to polyoxy second The cetostearyl ether of alkene 20 and polyoxyl 10 oleyl ether；DL-. α .- tocopherol polyethyleneglycol succinates, it can make For trade name is sold；Glycerine one-, two-and three-ester；C8-C22The glycerine one of aliphatic acid-, two-and three-ester；Sucrose one-, two-and Three -ester；The Sodium Caprylate of sulfosuccinic acid two；Pluronic F68, such as, but not limited to Pluronic/Lutrol F 44, pool Luo Shamu 188, poloxamer188；C8-C22The polyethenoxy ether class of fatty alcohol, include, but are not limited to polyoxyethylene lauryl alcohol, Polyoxyethylene cetyl alcohol, polyoxyethylene stearyl alcohol, polyoxyethylene oleyl alcohol, the trade name of its sale is for example35、58、7898；Or their any mixture of two or more.
Coemulsifier or cosurfactant can be used for preparation.Suitable coemulsifier or cosurfactant Agent can be phosphoglyceride；Phosphatide, such as lecithin or free fatty, it is at room temperature liquid, such as isostearic acid, Oleic acid, linoleic acid, leukotrienes, palmitic acid, stearic acid, laurate, capric acid, octanoic acid and caproic acid.
Suitable solvent/co-solvent includes ethanol, propane diols, polyethylene glycol, carbitol and glycerine.
Polymer can be used for preparation to suppress drug precipitation.Have confirmed that a range of adduct can influence this A little characteristics and be well known to the skilled person.Suitable polymer includes hydroxypropyl methyl cellulose, hydroxypropyl first Base cellulose acetyl base succinate, polymer such as methylcellulose derived from other celluloses；Poly- (methyl) acrylate Class, such as Eudragit series polymers, including Eudragit E100, polyvinylpyrrolidone or such as Warren et al. Mol.Pharmaceutics 2013,10, the other polymers described in 2823-2848.
Preparation can also include the material that the preparation with lipid as matrix generally known to those skilled in the art includes, example Such as Butylated Hydroxyanisole (BHA) or Butylated Hydroxytoluene (BHT) and curing agent, such as mesoporous silica, such as magnesium aluminometasilicate (Neusilin)。
In another embodiment, the compound can together with enzyme inhibitor oral administration increasing prodrug in stomach Stability in enteron aisle or enterocyte.In some embodiments, pay close attention to the enzyme inhibitor and suppress pancreatic lipase, example bag Include, but be not limited to Alli and orlistat.In other embodiments, pay close attention to the enzyme inhibitor and suppress cellular fat enzyme, example Such as an acylglycerol lipase, the example includes, but are not limited to JZL184 (4- nitrobenzophenones -4- [double (dioxies between 1,3- benzo Heterocyclic pentene -5- bases) (hydroxyl) methyl] piperidines -1- formic acid esters).
Notwithstanding the above compound or its pharmaceutically acceptable salt can be applied to single active component Subject, but other active components are applied together with the compound and belong to the scope of the present invention.In one or more implementations In scheme, the combined administration of two or more of compound of the invention is paid close attention in subject.
The present invention also provides pharmaceutical composition, its compound as defined above for including therapeutically effective amount or its pharmacy Upper acceptable salt and at least one pharmaceutically acceptable carrier or diluent.
Term " composition " expection includes the preparation of active component and the coating material as carrier, obtains capsule, wherein Active component (with or without another carrier) is surrounded by a carrier.
Just as easily understood by the skilled person, the property of pharmaceutically acceptable carrier depends on treated disease Disease and the property of mammal.Think that specific support or the selection of delivery system are readily determined by those skilled in the art.In system During standby any preparation comprising active mixture, should consider with caution, to ensure the activity of compound not in the process In be destroyed, and the compound can reach its site of action without being damaged.In some cases, it is necessary to by this area Known mode protects compound, for example, microencapsulation.
Those skilled in the art are easy to sample the suitable preparation that conventional method determines for the compounds of this invention.Identification is excellent The pH scopes of choosing and suitable excipient such as antioxidant are conventional this areas.Buffer system is usually used in providing expected range PH value, and including carboxylic acid buffer solution, such as acetate, citrate, lactate and succinate.Various antioxidants can To be used in this kind of preparation, including phenolic compound, such as BHT or vitamin E, reducing agent such as methionine or sulphite With metal-chelator such as EDTA.
Pharmaceutically acceptable medium and/or diluent include any and all of solvent, decentralized medium, are coated clothing Material, antiseptic and antifungal agent, etc. blend absorption delaying agent etc..The application of this kind of medium and reagent in pharmaceutically active substance is It is well-known in the art.Except any typical media or reagent are incompatible with active component, its answering in therapeutic combination Be considered.The active component that will can also be supplemented mixes composition.
Can also other therapeutic agents be applied in a joint manner with one or more by the compound.The combination can be single Solely, compound and other active components mentioned above are sequentially or simultaneously applied.Said composition can be with the shape of pharmaceutical composition Formula is provided.
Use herein, term " combination " refers to composition or external member product, wherein combination as defined above Companion can be applied with dependence or independent mode or be come by using the different fixed Combinations from the combined partner of difference consumption Using that is, simultaneously or in different time points administration.Then, it is right for example, can staggeredly apply combined partner simultaneously or chronologically In the different parts of external member, it can be applied at different time points and equivalent or different time interval.Applied in combination Combined partner total amount variable-scale, it is single for example, to meet the demand of patient subgroups to be treated or the demand of single patient The different demands of one patient can be attributed to age, sex, body weight of the patient etc..
The composition of preparation unit dosage forms is particularly advantageous, it is easy to apply and dose uniformity.Institute in the application Unit dosage forms refer to the physical dispersion unit of the dosage unit for being adapted as mammalian subject to be treated；Each list Active material of the unit comprising scheduled volume, is computed it and the desired treatment of generation is combined with required pharmaceutically acceptable medium Effect.Specified according to following factor for the specification of the new unit dosage forms of the present invention and directly depend on following factor：A () is living Property material specific characteristic and realized particular treatment effect；And be mixed for treating subject's living in (b) this area The inherent limitation of the active material of disease, the subject has ill condition, wherein in healthy such as the application in detail Retouch disclosed impaired.
As set forth above, it is possible to mix main active, with conveniently and efficiently with therapeutically effective amount and suitable pharmacy Upper acceptable medium is applied in unit dosage forms together.For example, unit dosage forms can comprising consumption be 0.25 μ g- about The main active of 2000mg.Proportionally represent, the amount of reactive compound is about 0.25 μ g- about 2000mg/mL loads Body.In the case of the composition comprising supplement active component, the common dose and method of application for being referred to the composition are true Determine dosage.
As used in this application, term " effective dose " refer to when according to desired dispenser scheme using when provide desired The compound amount of therapeutic activity.Dispenser can be spaced 1 time for 1 time or in several minutes or a few hours, or appointing in these time limits It is carried out continuously in meaning one.Suitable dosage can be in the scope of the about 0.1 nanogram/g kg of kg body weight -1 body weight/dosage. Typical doses are the g kg body weight of 1 microgram -1/dosage, such as 1 milligram -1 g kg body weight/dosage.In an embodiment In, the dosage can be 1 milligram of -500 mg/kg body weight/dosage.In another embodiment, the dosage can be 1 milli Gram -250 mg/kg body weight/dosage.In another embodiment, the dosage can be 1 milligram of -100 mg/kg body Weight/dosage, such as at most 50 milligrams/body weight/dosage.
Use herein, term " treatment " covers animal, preferably mammal, more preferably the illness of people or disease Any treatment, and increase the treatment for beneficial any disease or obstacle including wherein testosterone levels.Use herein, art Language " prevention " covers animal, preferably mammal, the more preferably prevention of the illness or disease of people, and increases including wherein testosterone levels Add as the prevention of beneficial any disease or obstacle.
The present invention is described referring now to following non-limiting examples.The following example is the representative of logical formula (I), and carries The method detailed for preparing exemplary compounds of the present invention is supplied.
The method that embodiment 1. is used for the compound for preparing formula (I), wherein Y represents unsubstituted alkyl and L represents X', Wherein X' is O.
A) 5- ((double (palm acyloxy) the propyl- 2- yls of 1,3-) epoxide) -5- oxopentanoic acids (IV)
4- (dimethylamino) pyridine (64.4mg, 0.527mmol) is added into diglyceride III (300mg, 0.527mmol) With glutaric anhydride I (120mg, 1.05mmol) in pyridine/THF/CH2Cl2In solution in (each 1.5mL), by the mixture in room Temperature stirring 2 days.The reaction system is diluted with ethyl acetate (20mL), is washed with 1M HCl and salt solution (each 20mL), dried (MgSO4), it is concentrated under reduced pressure, obtain crude product.Silica gel chromatography (10%-15% ethyl acetate/hexanes) is carried out, acid glycerol is obtained Three ester IV (140mg, 39%), are colorless solid.
1H NMR (400MHz, CDCl3) δ 5.26 (m, 1H), 4.31 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J= 11.9,5.9Hz, 2H), 2.44 (t, J=7.4Hz, 2H), 2.42 (t, J=7.4Hz, 2H), 2.31 (t, J=7.6Hz, 4H), 1.96 (pent, J=7.3Hz, 2H), 1.67-1.54 (m, 4H), 1.49-1.18 (m, 48H), 0.88 (t, J=6.8Hz, 6H).
B) suberoyl dichloro (II)
Suberic acid (84.2mg, 0.483mmol) and DMF (1 drop) is mixed in thionyl chloride (351 μ L, 4.83mmol) Compound is heated at reflux 1.5 hours.The reaction system is cooled to room temperature, is diluted with toluene (5mL), be concentrated under reduced pressure, obtain two acyls Chlorine II (102mg, quantitative), is yellow oil, not purified to use.
1H NMR (400MHz, CDCl3) δ 2.90 (t, J=7.2Hz, 4H), 1.78-1.68 (m, 4H), 1.42-1.35 (m, 4H)。
C) 8- ((double (palm acyloxy) the propyl- 2- yls of 1,3-) epoxide) -8- oxo octanoic acids (IV)
By diglyceride III (50.0mg, 0.0879mmol) and pyridine (71.1 μ L, 0.879mmol) in CH2Cl2(2mL) In solution add suberoyl dichloro II (102mg, 0.483mmol) in CH2Cl2In solution in (1.5mL), by the mixture It is stirred at room temperature 3.5 hours.The reaction system is cooled to room temperature, is diluted with water (10mL) and 1M HCl (3mL), use acetic acid second Ester (3 × 15mL) aqueous layer extracted.The organic extract for merging is washed with 1M HCl (30mL) and salt solution (2 × 30mL), is dried (MgSO4), it is concentrated under reduced pressure, obtain crude product.By Silica gel chromatography (20%-50% ethyl acetate/hexanes), acid is obtained Triglycerides IV (29.5mg, 46%), is faint yellow solid.
1H NMR (400MHz, CDCl3) δ 5.25 (m, 1H), 4.29 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J= 11.9,5.9Hz, 2H), 2.37-2.28 (m, 8H), 1.68-1.56 (m, 8H), 1.39-1.21 (m, 52H), 0.87 (t, J= 6.8Hz, 6H).
D) 10- (1,3- double (palm acyloxy) propyl- 2- yls) decanedioic acid 1- ((3R, 5S, 8S, 9S, 10S, 13S, 14S, 17S) hexahydro -1H- cyclopentano [a] phenanthrene -3- bases of -17- acetyl group -10,13- dimethyl -11- oxos ten) ester (2)
By 4- (dimethylamino) pyridine (DMAP, 5.2mg, 42.5 μm of ol), EDCHCl (20.4mg, 106 μm of ol) and Ah Method salon (22.6mg, 68.0 μm of ol) adds acid-TG IV (32.0mg, 42.5 μm of ol) in CH2Cl2In solution in (1.5mL), The mixture is stirred at room temperature 22 hours.Use CH2Cl2(5mL) dilutes the reaction system, adds silica gel, and be concentrated under reduced pressure the mixing Thing.By Silica gel chromatography (15%-20% ethyl acetate/hexanes), compound 2 (20.5mg, 45%) is obtained, be colourless Solid.
1H NMR (400MHz, CDCl3) δ 5.25 (m, 1H), 5.00 (m, 1H), 4.29 (dd, J=11.9,4.4Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 2.71 (t, J=9.0Hz, 1H), 2.56 (d, J=11.9Hz, 1H), 2.48 (d, J= 12.0Hz, 1H), 2.34-2.18 (m, 10H), 2.09 (s, 3H), 1.86-1.37 (m, 18H), 1.36-1.07 (m, 62H), 1.00 (s, 3H), 0.87 (t, J=6.8Hz, 6H), 0.57 (s, 3H).
E) 10- (1- ((tert-butoxycarbonyl) (isopropyl) amino) -3- (4- (2- methoxy ethyls) phenoxy group) propyl- 2- Base) decanedioic acid 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) ester (XXV)
4- (dimethylamino) pyridine (DMAP, 5.6mg, 45.4 μm of ol) and EDCHCl (17.4mg, 90.0 μm of ol) are added Enter previously prepared N-Boc- metoprolols (16.7mg, 45.4 μm of ol) and acid-TG IV (34.2mg, 45.4 μm of ol) in CH2Cl2 In solution in (2mL), the mixture is stirred at room temperature 19 hours.Then be concentrated under reduced pressure the reaction system, obtains crude product. By Silica gel chromatography (10%-25% ethyl acetate/hexanes), protected prodrug XXV (23.3mg, 47%) is obtained, It is colorless solid.
1H NMR (400MHz, CDCl3) δ 7.12 (d, J=8.5Hz, 2H), 6.83-6.78 (m, 2H), 5.33 (m, 1H), 5.25 (m, 1H), 4.29 (dd, J=11.9,4.4Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 4.22-3.98 (m, 3H), 3.55 (t, J=7.1Hz, 2H), 3.47 (m, 1H), 3.34 (s, 3H), 3.31 (m, 1H), 2.81 (t, J=7.1Hz, 2H), 2.33-2.27 (m, 8H), 1.64-1.56 (m, 8H), 1.46 (s, 9H), 1.37-1.20 (m, 56H), 1.18 (d, J=6.8Hz, 3H), 1.14 (d, J=6.7Hz, 3H), 0.87 (t, J=6.9Hz, 6H).
F) 10- (1- (isopropylamino) -3- (4- (2- methoxy ethyls) phenoxy group) propyl- 2- yls) decanedioic acid 1- (1,3- Double (palm acyloxy) propyl- 2- yls) ester (3)
By trifluoroacetic acid (TFA) (7.7 μ L, 0.104mmol) add Boc carbamates XXV (23.0mg, 0.0209mmol) in CH2Cl2In solution in (1mL), the reaction system is stirred at room temperature 6 hours.Now, TLC analyses are aobvious Show the slow progress of reaction, therefore add TFA (15.4 μ L, 0.208mmoL), the mixture is stirred for 18 hours in room temperature. Add triethylamine (Et3N, 50 μ L), in N2The reaction system is concentrated in air-flow, crude product is obtained.By Silica gel chromatography (contain 1%Et3The 20%-40%-60% ethyl acetate/hexanes of N), compound 3 (19.0mg, 91%) is obtained, it is water white oil Shape thing.
1H NMR (400MHz, CDCl3) δ 7.16-7.09 (m, 2H), 6.87-6.81 (m, 2H), 5.29-5.18 (m, 2H), 4.29 (dd, J=11.9,4.4Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 4.11-4.08 (m, 2H), 3.55 (t, J =7.1Hz, 2H), 3.34 (s, 3H), 2.99-2.88 (m, 2H), 2.86-2.77 (m, 3H), 2.35-2.28 (m, 8H), 1.69- 1.49 (m, 8H), 1.37-1.16 (m, 56H), 1.05 (d, J=6.2Hz, 6H), 0.88 (t, J=6.8Hz, 6H).
G) 10- (4- (6- hydroxyls -3- (4- (2- (piperidin-1-yl) ethyoxyl) benzoyl) benzo [b] thiophene -2- bases) Phenyl) decanedioic acid 1- (1,3- double (palm acyloxy) propyl- 2- yls) ester (4) synthesis：
In the case of Raloxifene (RAL), it includes two phenolic hydroxyl groups, parent molecule is carried out single protection be must Few, to prevent from being formed in subsequent Coupling step the monoacyl and double acyl group products of mixing.1 equivalent is used in the presence of base TBSCl treatment Raloxifenes obtain the mixture of the silyl ether of region isomer one, can be by its part by chromatography Separate.The relatively low phenol isomers XXVI of polarity and acid-TG IV are coupled obtain protected prodrug XXVII at the standard conditions.Make Silyl-protecting groups are removed with TBAF obtain compound 4.It should be noted that, it is also possible to it is using the method that the region of phenol XXVI is different Structure body changes into corresponding isomers prodrug.
G) (i) (6- ((t-butyldimethylsilyl) epoxide) -2- (4- hydroxy phenyls) benzo [b] thiene-3-yl) (4- (2- (piperidin-1-yl) ethyoxyl) phenyl) ketone (XXVI)
4- (dimethylamino) pyridine (DMAP, 108mg, 0.882mmol) is added in the hydrochloric acid thunder Lip river former times in DMF (10mL) In fragrant (180mg, 0.353mmol), the mixture is stirred at room temperature 1 hour.The reaction system is cooled to 0 DEG C, uncle is added Butyl (chlorine) dimethylsilane (TBSCl, 53.2mg, 0.353mmol), the mixture that will be obtained is stirred for 2.5 hours in room temperature. The reaction system is diluted with ethyl acetate (60mL), with water (2 × 50mL), saturation NaHCO3The aqueous solution (50mL) and salt solution (50mL) washs organic phase, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.(contain 1% by Silica gel chromatography Et3The 0%-12.5%MeOH/CH of N2Cl2), protected silyl ether XXVI (25.0mg, 12%) is obtained, it is yellow Grease, and the substantial amounts of silyl ether of Mixed Zone isomers one and unreacted Raloxifene fraction.
1H NMR (400MHz, CDCl3) δ 7.68 (d, J=8.8Hz, 2H), 7.47 (d, J=8.7Hz, 1H), 7.30 (d, J =2.0Hz, 1H), 7.22 (d, J=8.5Hz, 2H), 6.87 (dd, J=8.7,2.0Hz, 1H), 6.65 (d, J=7.9Hz, 4H), 4.06 (t, J=5.9Hz, 2H), 2.75 (t, J=5.9Hz, 2H), 2.55-2.47 (m, 4H), 1.65-1.58 (m, 4H), 1.48- 1.41 (m, 2H), 0.92 (s, 9H), 0.11 (s, 6H).
G) (ii) 10- (4- (6- ((t-butyldimethylsilyl) epoxide) -3- (4- (2- (piperidin-1-yl) ethoxies Base) benzoyl) benzo [b] thiophene -2- bases) phenyl) decanedioic acid 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) ester (XXVII)
4- (dimethylamino) pyridine (DMAP, 2.4mg, 19.9 μm of ol) and EDCHCl (9.5mg, 49.8 μm of ol) are added Acid-TG IV (15.0mg, 19.9 μm of ol) and XXVI (11.7mg, 19.9 μm of ol) are in CH2Cl2In solution in (0.6mL), by this Mixture is stirred at room temperature 6 hours.Use CH2Cl2(5mL) dilutes the reaction system, adds silica gel, and be concentrated under reduced pressure the mixture.It is logical Cross Silica gel chromatography and (contain 1%Et3The 0%-1.5%MeOH/CH of N2Cl2), obtain protected prodrug XXVII (16.0mg, 61%), is colorless oil.
1H NMR (400MHz, CDCl3) δ 7.74-7.67 (m, 3H), 7.59 (d, J=2.1Hz, 1H), 7.30-7.23 (m, 2H), 7.06 (dd, J=8.8,2.1Hz, 1H), 6.73 (d, J=8.8Hz, 2H), 6.67 (d, J=8.6Hz, 2H), 5.26 (m, 1H), 4.29 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 4.07 (t, J=6.0Hz, 2H), 2.74 (t, J=5.9Hz, 2H), 2.58 (t, J=7.5Hz, 2H), 2.53-2.44 (m, 4H), 2.35-2.27 (m, 6H), 1.82- 1.73 (m, 2H), 1.68-1.53 (m, 10H), 1.49-1.39 (m, 4H), 1.38-1.19 (m, 54H), 0.93 (s, 9H), 0.87 (t, J=6.8Hz, 6H), 0.12 (s, 6H).
G) (iii) 10- (4- (6- hydroxyls -3- (4- (2- (piperidin-1-yl) ethyoxyl) benzoyl) benzo [b] thiophene - 2- yls) phenyl) decanedioic acid 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) ester (4)
0 DEG C will fluorination tetra-n-butyl ammonium (THF solution of TBAF, 0.1M, 70.0 μ L, 7.0 μm of ol) and acetic acid (1.0M's THF solution, 10.0 μ L, 10.0 μm of ol) add TBS ethers XXVII (7.1mg, 5.4 μm of ol) solution in THF (0.4mL), The mixture is stirred 50 minutes at 0 DEG C.The reaction system is diluted with ethyl acetate (20mL), is washed with water and salt solution (15mL) Wash, dry (MgSO4), it is concentrated under reduced pressure, obtain crude product.1%Et (is contained by Silica gel chromatography3The 0%-2% of N MeOH/CH2Cl2), compound 4 (4.9mg, 75%) is obtained, it is pale yellow oil.
1H NMR (400MHz, CDCl3) δ 7.77 (d, J=8.8Hz, 1H), 7.66 (d, J=8.9Hz, 2H), 7.59 (d, J =2.1Hz, 1H), 7.19 (d, J=8.6Hz, 2H), 7.08 (dd, J=8.8,2.2Hz, 1H), 6.67 (d, J=7.3Hz, 2H), 6.61 (d, J=8.6Hz, 2H), 5.26 (m, 1H), 4.30 (dd, J=11.9,4.3Hz, 2H), 4.15 (dd, J=11.9, 5.9Hz, 2H), 4.09 (t, J=5.7Hz, 2H), 2.77 (t, J=5.8Hz, 2H), 2.62-2.50 (m, 6H), 2.37-2.27 (m, 6H), 1.82-1.73 (m, 2H), 1.69-1.55 (m, 10H), 1.50-1.19 (m, 58H), 0.87 (t, J=6.8Hz, 6H).
The method that embodiment 2. is used for the compound for preparing formula (I), wherein Y represents the alkyl of Alpha-Methyl substitution, and L is represented X', wherein X' are O.
H) (E) -10- (benzyloxy) -2- methyl decyl- 2- e pioic acid methyl esters (VIII)
By PCC(PCC, 39.7mg, 0.184mmol) and celite (Celite) (30mg) add alcohol VI (29.0mg, 0.123mmol) is in CH2Cl2In solution in (1.5mL), by the reaction, the system is stirred at room temperature 1.5 hours.It is logical The dark suspension that too short silicagel pad is filtrated to get, is eluted with 50% ethyl acetate/hexane, and be concentrated under reduced pressure eluent, obtains thick Aldehyde, is re-dissolved in toluene (1.5mL) at once.In addingSalt VII (85.5mg, 0.245mmol), the mixture is heated at reflux 20 hours.The reaction system is cooled to room temperature, is concentrated under reduced pressure, obtain crude product.By Silica gel chromatography (5%-8% Ethyl acetate/hexane), α is obtained, β-unsaturation methyl esters VIII (26.2mg, 70%), is yellow oil.
1H NMR (400MHz, CDCl3) δ 7.38-7.26 (m, 5H), 6.76 (m, 1H), 4.50 (s, 2H), 3.73 (s, 3H), 3.46 (t, J=6.6Hz, 2H), 2.10-2.02 (m, 2H), 1.83 (d, J=1.3Hz, 3H), 1.65-1.58 (m, 2H), 1.47- 1.28 (m, 8H).
I) (E) -10- (benzyloxy) -2- methyl decyl- 2- olefin(e) acids (IX)
Sodium hydroxide solution (2.0M, 256 μ L, 0.512mmol) is added in methyl alcohol (0.9mL) and water (0.65mL) In ester VIII (26.0mg.0.0854mmol), the mixture is stirred at room temperature 30 minutes, is then stirred 20 hours at 0 DEG C.It is logical Cross addition 1M HCl and the reaction system is acidified to pH 1, diluted with water (5mL), with ethyl acetate (4 × 15mL) aqueous phase extracted. The organic extract for merging is washed with salt solution (40mL), (MgSO is dried4), it is concentrated under reduced pressure, (24.8mg determines to obtain thick acid IX Amount), it is colorless oil, it is not purified to use.
1H NMR (400MHz, CDCl3) δ 7.39-7.26 (m, 5H), 6.91 (td, J=7.5,1.3Hz, 1H), 4.51 (s, 2H), 3.47 (t, J=6.6Hz, 2H), 2.23-2.15 (m, 2H), 1.83 (d, J=0.7Hz, 3H), 1.67-1.56 (m, 2H), 1.49-1.25 (m, 8H).
J) (E)-two palmitic acid 2- ((10- (the benzyloxy) -2- methyl decyl- 2- enoyl-s) epoxide) base esters of propyl- 1,3- bis- (X)
By 4- (dimethylamino) pyridine (DMAP, 10.4mg, 0.0854mmol), EDCHCl (40.9mg, 0.214mmol) Acid IX (24.8mg, 0.0854mmol) is added in CH with diglyceride III (77.7mg, 0.137mmol)2Cl2It is molten in (2mL) In liquid, the mixture is stirred at room temperature 17 hours.Use CH2Cl2(5mL) dilutes the reaction system, adds silica gel, is concentrated under reduced pressure The mixture.By Silica gel chromatography (3%-7.5% ethyl acetate/hexanes), obtain triglycerides X (44.6mg, 62%, 2 steps), it is colorless solid.
1H NMR (400MHz, CDCl3) δ 7.37-7.24 (m, 5H), 6.76 (m, 1H), 5.30 (m, 1H), 4.50 (s, 2H), 4.31 (dd, J=11.8,4.5Hz, 2H), 4.22 (dd, J=11.8,5.8Hz, 2H), 3.46 (t, J=6.6Hz, 2H), 2.31 (t, J=7.5Hz, 4H), 2.16 (dt, J=7.4,7.4Hz, 2H), 1.81 (d, J=1.1Hz, 3H), 1.66-1.55 (m, 6H), 1.47-1.19 (m, 56H), 0.88 (t, J=6.9Hz, 6H).
K) two palmitic acid 2- ((the 10- hydroxy-2-methyls capryl) epoxide) base esters of propyl- 1,3- bis- (XI)
The solution of benzylic ether X (40.0mg, 47.6 μm of ol) in ethyl acetate (5mL) in three-neck flask is taken out very It is empty 2 times, use N2Air-blowing is swept, and is subsequently adding palladium on carbon (10%w/w, 12.7mg, 11.9 μm of ol), and the suspension that will be obtained is taken out again Vacuum, uses N2Purging 2 times.H is equipped with to flask2Air bag, vacuumizes, and uses H2Purging 3 times, the reactant mixture is existed in room temperature The H of 1atm2Stirred 3 hours in atmosphere.The reaction system is filtered by celite pad, is washed with ethyl acetate, be concentrated under reduced pressure, obtained Saturated alcohols XI (32.1mg), is colorless oil, not purified to use.
1H NMR (400MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J=11.7,3.9Hz, 2H), 4.14 (dd, J= 11.9,6.1Hz, 2H), 3.63 (t, J=6.6Hz, 2H), 2.44 (m, 1H), 2.30 (t, J=7.6Hz, 4H), 1.67-1.50 (m, 8H), 1.42-1.20 (m, 58H), 1.14 (d, J=7.0Hz, 3H), 0.88 (t, J=6.9Hz, 6H).
L) two palmitic acid 2- ((the 2- methyl isophthalic acid 0- oxo-decanoyls base) epoxide) base esters of propyl- 1,3- bis- (XII)
At 0 DEG C by PCC(PCC, 15.2mg, 70.4 μm of ol) adds alcohol XI (26.5mg, 35.2 μm of ol) and C Salt (20mg) is in CH2Cl2In suspension in (1mL), the mixture is stirred at room temperature 1 hour.Being filtered by short silicagel pad should Reaction system, is eluted with 50% ethyl acetate/hexane, and be concentrated under reduced pressure filtrate, obtains thick aldehyde XII (26.4mg), is yellow oily Thing, it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 9.76 (t, J=1.8Hz, 1H), 5.27 (m, 1H), 4.29 (ddd, J=11.9, 4.3,3.1Hz, 2H), 4.14 (dd, J=11.9,6.1Hz, 2H), 2.42 (m, 1H), 2.41 (td, J=7.3,1.8Hz, 2H), 2.30 (t, J=7.5Hz, 4H), 1.67-1.54 (m, 8H), 1.44-1.18 (m, 56H), 1.14 (d, J=7.0Hz, 3H), 0.88 (t, J=6.9Hz, 6H).
M) 10- ((double (palm acyloxy) the propyl- 2- yls of 1,3-) epoxide) -9- methyl isophthalic acids 0- oxos capric acid (IV)
By sodium chlorite (28.6mg, 0.317mmol) and sodium dihydrogen phosphate (NaH2PO4, 29.5mg, 0.246mmol) and in water Solution in (0.5mL) be added drop-wise in t-BuOH (1mL) and 2,3- dimethyl -2- butylene (0.2mL) aldehyde XII (26.4mg, In 0.0352mmol), the reaction system is stirred at room temperature 1.5 hours.The reaction system is diluted with water (5mL), with hexane (3 × 5mL) aqueous layer extracted.Dry the organic extract (MgSO for merging4), it is concentrated under reduced pressure, thick acid IV (27.0mg) is obtained, it is colourless Grease, it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (ddd, J=11.8,4.3,3.2Hz, 2H), 4.14 (dd, J=11.9,6.1Hz, 2H), 2.43 (m, 1H), 2.36-2.28 (m, 6H), 1.65-1.55 (m, 8H), 1.38-1.19 (m, 56H), 1.14 (d, J=7.0Hz, 3H), 0.88 (t, J=7.0Hz, 6H).
The method that embodiment 3. is used for the compound for preparing formula (I), wherein Y represents the alkyl of Beta-methyl substitution, and L is represented X', wherein X' are O.
N) (7- (benzyloxy) hept- 1- alkynes -1- bases) trimethyl silane (XIV)
N-BuLi (hexane solution of n-BuLi, 1.6M, 765 μ L, 1.23mmol) is slowly added into TMS- at -78 DEG C In solution of the acetylene (198 μ L, 1.40mmol) in THF (1.5mL), the mixture is stirred 5 minutes at -78 DEG C, Ran Houwen Heat is stirred for 15 minutes to room temperature.The reaction system is cooled to -50 DEG C, be added dropwise bromide XIII (90.0mg, 0.350mmol) the solution in THF (1mL), the mixture is stirred 15 minutes at -50 DEG C, is then stirred at room temperature 17 small When.The reaction system is diluted with salt solution (15mL), with ethyl acetate (3 × 15mL) aqueous phase extracted.Conjunction is washed with salt solution (30mL) And organic extract, dry (MgSO4), it is concentrated under reduced pressure, obtain crude product.By Silica gel chromatography (4%-5% acetic acid Ethyl ester/hexane), TMS alkynes XIV (45.9mg, 48%) is obtained, it is colorless oil, its also alkynes XV comprising removal monosilane base (9.7mg passes through114%) and a small amount of PPh H NMR grades is divided into3。
1H NMR (400MHz, CDCl3) δ 7.37-7.26 (m, 5H), 4.50 (s, 2H), 3.48 (t, J=6.5Hz, 2H), 2.23 (t, J=7.0Hz, 2H), 1.68-1.60 (m, 2H), 1.58-1.42 (m, 4H), 0.14 (s, 7H).
O) ((hept- 6- alkynes -1- bases epoxide) methyl) benzene (XV)
Tetrabutylammonium (THF solution of TBAF, 1.0M, 201 μ L, 0.201mmol) is added drop-wise to silicyl at 0 DEG C Alkynes XIV and alkynes XV (merging 55.6mg, 0.215mmol) in THF (1mL) 7：In 2 mixtures, the mixture is stirred in room temperature Mix 1 hour.With water (5mL) and saturated aqueous solution NH4Cl (3mL) dilutes the reaction system, is extracted with ethyl acetate (3 × 10mL) Water phase.The organic extract for merging is washed with salt solution (20mL), (MgSO is dried4), it is concentrated under reduced pressure, obtain crude product.By silicon Glue chromatography purifies (4% ethyl acetate/hexane), obtains alkynes XV (37.5mg, 53%, 2 step), is colorless oil.
1H NMR (400MHz, CDCl3) δ 7.39-7.27 (m, 5H), 4.51 (s, 2H), 3.49 (t, J=6.5Hz, 2H), 2.21 (td, J=6.9,2.6Hz, 2H), 1.95 (t, J=2.7Hz, 1H), 1.70-1.61 (m, 2H), 1.60-1.48 (m, 4H).
P) (Z) -10- (benzyloxy) -3- methyl decyl- 2- alkene -4- ynoic acid ethyl esters (XVII)
Use N2Gas is to PdCl2(PPh3)2The suspension of (16.8mg, 0.0240mmol) in DMF (1.5mL) deaerates 5 points Clock, is subsequently adding CuI (9.1mg, 0.0480mmol), Et in DMF (2mL)3N (66.8 μ L, 0.480mmol) and degassing Alkynes XV (48.5mg, 0.240mmol) and TFMS enol ester XVI (94.3mg, 0.360mmol).Use N2Air-flow is given should Mixture deaerates 5 minutes again, is then heated 1 hour at 0 DEG C.The reaction system is cooled to room temperature, with ethyl acetate (30mL) Dilution, with 1M HCl, saturated aqueous solution NaHCO3, water and salt solution (each 20mL) washing, dry (MgSO4), it is concentrated under reduced pressure, obtain Crude product.Silica gel chromatography (4%-5% ethyl acetate/hexanes) is carried out, eneyne XVII (46.6mg, 62%) is obtained, is yellowish Color grease.
1H NMR (400MHz, CDCl3) δ 7.37-7.24 (m, 5H), 5.92 (m, 1H), 4.50 (s, 2H), 4.17 (q, J= 7.1Hz, 2H), 3.48 (t, J=6.5Hz, 2H), 2.45 (t, J=7.0Hz, 2H), 2.01 (d, J=1.4Hz, 3H), 1.69- 1.59 (m, 4H), 1.56-1.49 (m, 2H), 1.27 (t, J=7.1Hz, 3H).
Q) 10- hydroxy-3-methyls ethyl caprate (XVIII)
Give solution of the benzylic ether XVII (31.4mg, 0.100mmol) in double-neck flask in ethyl acetate (8mL) Vacuumize 2 times, use N2Air-blowing is swept, and is subsequently adding palladium on carbon (10%w/w, 26.6mg, 0.0250mmol), the suspension that will be obtained Vacuumize again, use N2Purging 3 times.H is equipped with to flask2Air bag, vacuumizes, and uses H2Purging 3 times, by the reactant mixture in room temperature In 1atm H2Stirred 1 hour in atmosphere.The reaction system is filtered by celite pad, is washed with ethyl acetate, be concentrated under reduced pressure, obtained Saturated alcohols XVIII (23.0mg, quantitative), is colorless oil, and it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 4.12 (q, J=7.1Hz, 2H), 3.63 (t, J=6.6Hz, 2H), 2.28 (dd, J =14.6,6.1Hz, 1H), 2.09 (dd, J=14.6,8.1Hz, 1H), 1.94 (m, 1H), 1.60-1.50 (m, 2H), 1.25 (t, J=6.6Hz, 3H), 1.40-1.13 (m, 10H), 0.92 (d, J=6.6Hz, 3H).
R) 10- ((t-butyldiphenylsilyl) epoxide) -3- methyl ethyl caprate (XIX)
By imidazoles (9.6mg, 0.141mmol) and the tert-butyl group (chlorine) diphenyl silane (TBDPSCl, 50.8 μ L, 0.195mmol) in solution of addition alcohol XVIII (18.0mg, 0.0781mmol) in DMF (3mL), by the mixture in room temperature Stirring 16 hours.The reaction system is diluted with (20mL) ethyl acetate, is washed with salt solution (2 × 15mL), dry (MgSO4), subtract Pressure concentration, obtains crude product.0.5%Et (is contained by Silica gel chromatography34% ethyl acetate/hexane of N), obtain TBDPS ethers XIX (33.7mg, 92%), is colorless oil.
1H NMR (400MHz, CDCl3) δ 7.70-7.64 (m, 4H), 7.45-7.33 (m, 6H), 4.13 (q, J=7.1Hz, 2H), 3.65 (t, J=6.5Hz, 2H), 2.28 (dd, J=14.6,6.0Hz, 1H), 2.09 (dd, J=14.6,8.2Hz, 1H), 1.94 (m, 1H), 1.60-1.50 (m, 2H), 1.38-1.21 (m, 3H), 1.05 (s, J=2.9Hz, 2H), 1.05 (s, 9H), 0.93 (d, J=6.6Hz, 3H).
S) 10- ((t-butyldiphenylsilyl) epoxide) -3- methyl capric acid (XX)
Potassium hydroxide solution (2.0M, 427 μ L, 0.853mmol) is added in the ester XIX in ethanol (2mL) In (40.0mg.0.0853mmol), the mixture is heated 2 hours at 80 DEG C.By adding 1M HCl by reaction system acid Change to pH 1, organic solvent is removed under reduced pressure.Residue is diluted with water (5mL), with ethyl acetate (3 × 15mL) aqueous phase extracted, is used The organic extract that salt solution (30mL) washing merges, dries (MgSO4), it is concentrated under reduced pressure, thick acid XX (37.6mg, quantitative) is obtained, It is colorless oil, uses without further purification.When running in higher concentrations, it was observed that1H and13Letter in C NMR spectras Number multiplication (4：The ratio between 1) may there is monomer and dimerization material in solution in, this enlightenment.
1H NMR (400MHz, CDCl3) δ 7.74-7.63 (m, 4H), 7.45-7.34 (m, 6H), 3.65 (t, J=6.5Hz, 2H), 2.35 (dd, J=15.0,5.9Hz, 1H), 2.14 (dd, J=15.0,8.2Hz, 1H), 1.95 (m, 1H), 1.61-1.50 (m, 2H), 1.38-1.18 (m, 10H), 1.04 (s, 9H), 0.96 (d, J=6.6Hz, 3H).
T) two palmitic acid 2- ((10- ((t-butyldiphenylsilyl) epoxide) -3- methyl capryl) epoxide) propyl- 1, The base esters of 3- bis- (XXI)
By 4- (dimethylamino) pyridine (DMAP, 10.1mg, 0.0831mmol), EDCHCl (39.8mg, 0.208mmol) Sour XX (36.6mg, 0.0831mmol) is heated in CH with diglyceride III (70.9mg, 0.125mmol)2Cl2In (2.5mL) Solution in, the mixture is stirred at room temperature 21 hours.Use CH2Cl2(5mL) dilutes the reaction system, adds silica gel, decompression Concentrate the mixture.By Silica gel chromatography (4%-5% ethyl acetate/hexanes), obtain triglycerides XXI (39.9mg, 48%, 2 steps), it is colorless solid.
1H NMR (400MHz, CDCl3) δ 7.69-7.64 (m, 4H), 7.44-7.34 (m, 6H), 5.28 (m, 1H), 4.29 (ddd, J=11.8,4.2,0.6Hz, 2H), 4.14 (dd, J=12.0,5.9Hz, 2H), 3.65 (t, J=6.5Hz, 2H), 2.37-2.27 (m, 5H), 2.11 (dd, J=14.7,8.4Hz, 1H), 1.92 (m, 1H), 1.67-1.50 (m, 8H), 1.39- 1.14 (m, 56H), 1.04 (s, 9H), 0.93 (d, J=6.6Hz, 3H), 0.88 (t, J=6.9Hz, 6H).
U) two palmitic acid 2- ((the 10- hydroxy-3-methyls capryl) epoxide) base esters of propyl- 1,3- bis- (XI)
Tetrabutylammonium (THF solution of TBAF, 1.0M, 98.3 μ L, 98.3 μm of ol) is added into TBDPS ethers XXI at 0 DEG C In the solution of (39.0mg, 39.3 μm of ol) in THF (2.5mL), the mixture is stirred at room temperature 3 hours.With water (10mL) The reaction system is diluted, is extracted with ethyl acetate (3 × 15mL), organic extract is washed with salt solution (30mL), dried (MgSO4), it is concentrated under reduced pressure, obtain crude product.By Silica gel chromatography (10%-20% ethyl acetate/hexanes), alcohol is obtained XI (21.8mg, 74%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 5.28 (m, 1H), 4.29 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J= 11.9,5.9Hz, 2H), 3.64 (t, J=6.6Hz, 2H), 2.36-2.27 (m, 5H), 2.12 (dd, J=14.7,8.2Hz, 1H), 1.93 (m, 1H), 1.65-1.52 (m, 6H), 1.39-1.16 (m, 58H), 0.93 (d, J=6.6Hz, 3H), 0.88 (t, J= 6.9Hz, 6H).
V) two palmitic acid 2- ((the 3- methyl isophthalic acid 0- oxo-decanoyls base) epoxide) base esters of propyl- 1,3- bis- (XII)
At 0 DEG C by PCC(PCC, 12.0mg, 55.8 μm of ol) adds alcohol XI (21.0mg, 27.9 μm of ol) and C Salt (15mg) is in CH2Cl2In suspension in (1.5mL), the mixture is stirred at room temperature 1.75 hours.By short silicagel pad The reaction system is filtered, with wash-out ethyl acetate, be concentrated under reduced pressure filtrate, obtain thick aldehyde XII (20.9mg, quantitative), be yellow oil Shape thing, it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 9.76 (s, 1H), 5.28 (m, 1H), 4.29 (dd, J=11.6,3.5Hz, 2H), 4.14 (dd, J=11.6,5.7Hz, 2H), 2.42 (t, J=7.1Hz, 2H), 2.36-2.25 (m, 5H), 2.12 (dd, J= 14.5,8.3Hz, 1H), 1.93 (m, 1H), 1.72-1.53 (m, 6H), 1.42-1.05 (m, 56H), 0.93 (d, J=6.5Hz, 3H), 0.88 (t, J=6.6Hz, 6H).
W) 10- ((double (palm acyloxy) the propyl- 2- yls of 1,3-) epoxide) -8- methyl isophthalic acids 0- oxos capric acid (IV)
By sodium chlorite (22.7mg, 0.251mmol) and sodium dihydrogen phosphate (NaH2PO4, 23.4mg, 0.195mmol) and in water Solution in (1mL) be added drop-wise in t-BuOH (1.5mL) and 2,3- dimethyl -2- butylene (0.3mL) aldehyde XII (20.9mg, In 0.0279mmol), the reaction system is stirred at room temperature 2.25 hours.The reaction system is diluted with water (10mL), acetic acid is used Ethyl ester (3 × 15mL) aqueous layer extracted.The organic extract for merging is washed with salt solution (30mL), (MgSO is dried4), it is concentrated under reduced pressure, Obtain crude product.By Silica gel chromatography (the 10%-20% ethyl acetate/hexanes containing 0.5%AcOH), sour IV is obtained (16.1mg, 75%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J= 12.0,6.0Hz, 2H), 2.37-2.27 (m, 7H), 2.12 (dd, J=14.7,8.2Hz, 1H), 1.93 (m, 1H), 1.67-1.55 (m, 6H), 1.40-1.14 (m, 56H), 0.93 (d, J=6.6Hz, 3H), 0.88 (t, J=6.9Hz, 6H).
X) 10- ((8R, 9S, 10R, 13S, 14S, 17S) -10,13- dimethyl -3- oxo -2,3,6,7,8,9,10,11, Tetrahydrochysene -1H- cyclopentano [a] phenanthrene -17- bases of 12,13,14,15,16,17- ten) 3- methyl decanedioic acid 1- (double (the palm acyl-oxygens of 1,3- Base) propyl- 2- yls) ester (19)
By 4- (dimethylamino) pyridine (DMAP, 2.5mg, 20.6 μm of ol), EDCHCl (9.9mg, 51.4 μm of ol) and testis Ketone (10.7mg, 37.1 μm of ol) adds acid-TG IV (13.6mg, 17.7 μm of ol) in CH2Cl2In solution in (1mL), this is mixed Compound is stirred at room temperature 17 hours.Use CH2Cl2(5mL) dilutes the reaction system, adds silica gel, and be concentrated under reduced pressure the mixture.It is logical Silica gel chromatography (15% ethyl acetate/hexane) is crossed, compound 19 (10.1mg, 55%) is obtained, is colorless solid.
1H NMR (400MHz, CDCl3) δ 5.73 (s, 1H), 5.27 (m, 1H), 4.61 (dd, J=9.0,7.9Hz, 1H), 4.29 (dd, J=11.9,3.8Hz, 2H), 4.14 (dd, J=11.9,6.0Hz, 2H), 2.48-2.24 (m, 11H), 2.23- 1.99 (m, 4H), 1.93 (m, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.72-1.22 (m, 68H), 1.19 (s, 3H), 1.16- 0.96 (m, 4H), 0.93 (d, J=6.6Hz, 3H), 0.88 (t, J=6.9Hz, 6H), 0.83 (s, 3H).
The compound of the formula (I) of other examples is provided in table 4 below.
The representational compound of the following formula of table 4.1H NMR datas：
The method that embodiment 4. is used for the compound for preparing formula (I), wherein Z represents C (O) R3, R3Represent that acetal self is ruined The group for going out, and L represents that X', wherein X' are O or N (R4)。
Scheme 5：The synthesis of the compound with the suicidal linker of acetal
In order to synthesize comprising the change positioned at the acetal self-destruction linker of pharmaceutically active agents and alkyl spacer between Compound, be conducive to parent molecule systematicness release (Wittman, M.D. et al. Bioorg.Med.Chem.Lett.2001, 11,811-814), the pharmaceutically active agents with alcohol must functionalised and activate, then as outlined in scheme 5 with acid-it is sweet Three ester IV of oil are conjugated.Alcohol is processed with DMSO result in (methyl mercapto) methyl (MTM) ether in the mixture of acetic anhydride and acetic acid XXVIII.The sulfoxide species of presumption is formed using sulphonyl chlorine activation MTM ethers, it can be anti-with the carboxylate of acid-triglycerides IV Should, obtain the compounds X XIX with acetal.
Y) (8R, 9S, 10R, 13S, 14S, 17S) -10,13- dimethyl -17- ((methyl mercapto) methoxyl group) -1,2,6,7,8, 9,10,11-12,13,14,15,16,17- ten tetrahydrochysene -3H- cyclopentano [a] phenanthrene -3- ketone (XXVIII)
By acetic acid (44 μ L, 0.769mmol) and acetic anhydride (140 μ L, 1.48mmol) be added in DMSO (216 μ L, In testosterone (36.1mg, 0.125mmol) in 3.04mmol), the mixture is stirred at room temperature 2 days and 18 hours.It is now right The lcms analysis of the reactant mixture are shown without unreacted testosterone and 55% conversion ratio for obtaining desired MTM ethers, wherein greatly Measure other Plant composition material balances comprising testosterone.Under appropriate different condition total 5 secondary responses (ginseng is carried out with same levels See the table below), it is then combined with for separating desired product.The reactant mixture for merging is diluted with water (15mL), 10%K is used2CO3 Solution is neutralized.With ethyl acetate (3 × 20mL) aqueous phase extracted, saturated aqueous solution NaHCO is used3(40mL) and salt solution (40mL) are washed The organic extract of merging, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.(contain 1% by Silica gel chromatography Et3The 10%-15% ethyl acetate/hexanes of N), testosterone MTM ethers XXVIII (113mg, 52%) are obtained, it is faint yellow solid.
Solvent mixture：A=54:35:11v/v DMSO:Ac2O:AcOH (amounts to 400 μ L)
B=1.2:1:0.8v/v DMSO:Ac2O:AcOH (amounts to 375 μ L)
1H NMR (400MHz, CDCl3) δ 5.73 (s, 1H), 4.67 (d, J=11.2Hz, 1H), 4.58 (d, J=11.2Hz, 1H), 3.68 (t, J=8.4Hz, 1H), 2.48-2.24 (m, 4H), 2.13 (s, 3H), 2.08-1.97 (m, 2H), 1.93-1.80 (m, 2H), 1.75-1.22 (m, 8H), 1.19 (s, 3H), 1.07-0.90 (m, 3H), 0.82 (s, 3H).
Z) (((8R, 9S, 10R, 13S, 14S, 17S) -10,13- dimethyl -3- oxo -2,3,6,7-8,9,10,11,12, Tetrahydrochysene -1H- cyclopentano [a] phenanthrene -17- bases of 13,14-15,16,17- ten) epoxide) methyl adipic acid 1,3- pairs (palm acyloxy) Propyl- 2- base esters (21)
At 0 DEG C by the sulfonic acid chloride (CH of 0.81M2Cl2Solution, 100 μ L, 80.9 μm of ol) addition MTM ethers XXVIII (22.3mg, 63.9 μm of ol) in CH2Cl2In solution in (0.8mL), the reaction system is stirred 30 minutes at 0 DEG C, then stirred again in room temperature Mix 1 hour.In N2The reaction system, drying under reduced pressure are concentrated in air-flow.Then thick residue is re-dissolved in CH2Cl2(0.8mL), plus Enter the acid-TG IV (29.7mg, 42.6 μm of ol) and DBU (7.6 μ L, 51.1 μm of ol) of stirring 20 minutes in advance at toluene (0.8mL) In solution in, the mixture is stirred at room temperature 1.5 hours.Use CH2Cl2(20mL) dilutes the reaction system, uses saturation NaHCO3The aqueous solution (15mL) and salt solution (15mL) washing organic phase, dry (MgSO4), it is concentrated under reduced pressure, obtain crude product.Pass through Silica gel chromatography (10%-12.5% ethyl acetate/hexanes), obtains compound 21 (18.8mg, 44%), is pale yellow colored solid Body.
1H NMR (400MHz, CDCl3) δ 5.72 (s, 1H), 5.30-5.21 (m, 3H), 4.29 (dd, J=11.9,4.4Hz, 2H), 4.13 (dd, J=11.6,5.5Hz, 2H), 3.53 (dd, J=8.3,8.3Hz, 1H), 2.48-2.22 (m, 12H), 2.08- 1.98 (m, 2H), 1.92-1.80 (m, 2H), 1.75-1.50 (m, 13H), 1.49-1.20 (m, 49H), 1.18 (s, 3H), 1.17- 0.83 (m, 5H), 0.87 (t, J=6.9Hz, 6H), 0.79 (s, 3H).
Scheme 6. has the synthesis of the amine prodrug of the modified suicidal linker of acetal.
In this case, wherein pharmaceutically active agents include primary or secondary amine, it is possible to use the acetal of modified forms self is ruined The group for going out, wherein also including carbamate attachment (referring to scheme 6).Amine obtains amino first with chloro-methyl-chloroformate reaction Sour chloromethyl ester XXX.Then left away by processing displacement halide with the carboxylate derived from acid-TG IV in the toluene of backflow Base, the ASI prodrugs XXXI for being modified.
Aa) ((1S, 4S) -4- (3,4- dichlorophenyls) -1,2,3,4- naphthane -1- bases) (methyl) carbamic acid chloromethyl ester (XXX)
Chloro-methyl-chloroformate (8.3 μ L, 93.3 μm of ol) and pyridine (14.1 μ L, 175 μm of ol) are added into hydrochloric acid sertraline at 0 DEG C Woods (20.0mg, 58.3 μm of ol) is in CH2Cl2In solution in (4.5mL), the mixture is stirred 30 minutes at 0 DEG C, Ran Hou It is stirred at room temperature 4 hours.Use CH2Cl2(20mL) dilutes the reaction system, uses saturation NaHCO3The aqueous solution (2 × 20mL) and salt solution (each 20mL) washs organic phase, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.By Silica gel chromatography (10%- 15% ethyl acetate/hexane), carbamic acid chloromethyl ester XXX (20.5mg, 88%) is obtained, it is colorless solid.
1H NMR (400MHz, CDCl3) δ 7.34 (d, J=8.3Hz, 1H), 7.29 (m, 1H), 7.23-7.19 (m, 2H), 7.08 (s, br, 1H), 6.97 (m, 1H), 6.81 (m, 1H), 5.93-5.83 (m, 2H), 5.51 (dd, J=10.5,6.4Hz, 0.6H), 5.33 (m, 0.4H), 4.20 (m, 1H), 2.77 (s, 1.2H), 2.72 (s, 1.8H), 2.29 (m, 1H), 2.02 (m, 1H), 1.79 (m, 2H).Note：Fraction is integrated and reflects presence~3：2 rotamer mixture, this is attributed to limited Around the rotation of N- methyl carbamates functional group.
Ab) 3- methylglutaric acids 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) 5- (((((1S, 4S) -4- (3,4- dichloros Phenyl) -1,2,3,4- naphthane -1- bases) (methyl) carbamoyl) epoxide) methyl) ester (7)
By -7- the alkene (DBU) of 1,8- diazabicyclos [5.4.0] 11 (8.6 μ L, 57.2 μm of ol) and iodate tetra-n-butyl ammonium (TBAI, 5.8mg,) add acid-TG IV (20.5mg, 29.4 μm of ol) and chloromethylether XXX (11.8mg, 29.6 μm ol) in solution in toluene (1.5mL), the mixture is heated at reflux 3 hours.The reaction system is cooled to room temperature, Diluted with ethyl acetate (15mL), organic phase is washed with water (3 × 15mL) and salt solution (2 × 15mL), dry (MgSO4), decompression Concentration, obtains crude product.Carry out silica gel chromatography (10%-20% ethyl acetate/hexanes), obtain compound 7 (21.1mg, 68%), it is colorless oil.
1H NMR (400MHz, CDCl3) δ 7.33 (d, J=8.3Hz, 1H), 7.31-7.27 (m, 1H), 7.21-7.16 (m, 2H), 7.09 (d, J=2.0Hz, 1H), 6.96 (d, J=7.2Hz, 1H), 6.80 (td, J=8.0,2.0Hz, 1H), 5.89- 5.82 (m, 2H), 5.49 (dd, J=10.3,6.5Hz, 0.6H), 5.37-5.30 (m, 0.4H), 5.27 (m, 1H), 4.33-4.25 (m, 2H), 4.19 (m, 1H), 4.15-4.10 (m, 2H), 2.74 (s, 1.2H), 2.69 (s, 1.8H), 2.54-2.39 (m, 3H), 2.36-2.23 (m, 3H), 2.30 (t, J=7.5Hz, 4H), 2.01 (m, 1H), 1.84-1.70 (m, 2H), 1.66-1.57 (m, 4H), 1.33-1.20 (m, 48H), 1.05 (d, J=6.2Hz, 2H), 1.02 (d, J=6.0Hz, 1H), 0.88 (t, J=6.9Hz, 6H).Note：Fraction is integrated and reflects presence~3：2 rotamer mixture, this is attributed to limited around N- methyl ammonia Carbamate functional groups rotate.
The method that embodiment 5. is used for the compound for preparing formula (I), wherein Z represents C (O) R3, and R3Represent trimethyl lock certainly The group that I destroys, and L represents that X', wherein X' are O, NR4Or S (O)2NH。
Scheme 7. locks the synthesis of the compound of suicidal linker with trimethyl.
In order to synthesize prodrug (Levine, M.N. comprising ' trimethyl lock ' (TML) suicidal linker；Raines, R.T.Chem.Sci.2012,3,2412-2420), the linker is also located between pharmaceutically active agents and alkyl spacer base, to have Beneficial to the system release of parent molecule, it is necessary to make acid-triglycerides IV functionalizations with TML parts, then as outlined in scheme 7 With pharmaceutically active agents be conjugated.Acid-TG IV and TML phenol XXXII is coupled obtains triglycerides XXXIII at the standard conditions, can Desired sour XXXVI is converted it into according to similar mode described in scheme 4.Can (10- camphors in acid condition Sulfonic acid) make TBS ether XXXIII deprotections, aoxidize the alcohol XXXIV for obtaining with 2- footworks, obtain sour XXXVI.Then can be in mark With the pharmaceutically active agents coupling comprising alcohol, amine or sulfonamide under the conditions of standard, target compound XXXVII is obtained.
Ac) (2- (4- ((t-butyldimethylsilyl) epoxide) -2- methyl butyl- 2- yls) -3,5- 3,5-dimethylphenyls) Double (palm acyloxy) propyl- 2- base esters (XXXIII) of adipic acid 1,3-
4- (dimethylamino) pyridine (DMAP, 4.0mg, 33.1 μm of ol) and EDCHCl (12.6mg, 66.2 μm of ol) are added Enter acid-TG IV (30.0mg, 43.0 μm of ol) and phenol XXXII (10.7mg, 33.1 μm of ol) in CH2Cl2In solution in (1mL), The mixture is stirred at room temperature 16 hours.Use CH2Cl2(5mL) dilutes the reaction system, adds silica gel, and be concentrated under reduced pressure the mixing Thing.By Silica gel chromatography (4%-6% ethyl acetate/hexanes), obtain TML triglycerides XXXIII (19.8mg, 59%), it is colorless oil.
1H NMR (400MHz, CDCl3) δ 6.80 (d, J=2.0Hz, 1H), 6.52 (d, J=1.9Hz, 1H), 5.27 (m, 1H), 4.31 (dd, J=11.9,4.3Hz, 2H), 4.15 (dd, J=11.9,5.9Hz, 2H), 3.47 (t, J=7.5Hz, 1H), 2.55 (t, J=7.1Hz, 2H), 2.51 (s, 3H), 2.39 (t, J=7.0Hz, 2H), 2.31 (t, J=7.6Hz, 4H), 2.22 (s, 3H), 2.02 (t, J=7.5Hz, 1H), 1.82-1.72 (m, 4H), 1.65-1.56 (m, 4H), 1.45 (s, 6H), 1.36- 1.20 (m, 48H), 0.88 (t, J=6.9Hz, 6H), 0.84 (s, 9H), -0.03 (s, 6H).
Ad) (2- (4- hydroxy-2-methyl butyl- 2- yls) -3,5- 3,5-dimethylphenyls) adipic acid 1,3- is double (palm acyloxy) Propyl- 2- base esters (XXXIV)
The solution (the MeOH solution of 0.122M, 10 μ L, 1.2 μm of ol) of 10- camphorsulfonic acids is added in CH2Cl2(0.4mL) In the TBS ethers XXXIII (6.1mg, 6.1 μm of ol) in MeOH (0.4mL), the mixture is stirred at room temperature 1 hour.Use water (5mL) dilutes the reaction system, with (3 × 10mL) ethyl acetate aqueous layer extracted.Use saturated aqueous solution NaHCO3It is (each with salt solution 20mL) the organic extract that washing merges, dries (MgSO4), it is concentrated under reduced pressure, crude glycol XXXIV (6.1mg, quantitative) is obtained, it is nothing Color grease, it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 6.82 (d, J=1.4Hz, 1H), 6.53 (d, J=1.2Hz, 1H), 5.27 (m, 2H), 4.31 (dd, J=11.9,4.3Hz, 2H), 4.15 (dd, J=11.9,5.8Hz, 2H), 3.53 (t, J=7.2Hz, 2H), 2.58 (t, J=7.0Hz, 2H), 2.52 (s, 3H), 2.40 (t, J=6.9Hz, 2H), 2.31 (t, J=7.6Hz, 4H), 2.23 (s, 3H), 2.04 (t, J=7.2Hz, 2H), 1.82-1.72 (m, 4H), 1.65-1.53 (m, 4H), 1.48 (s, 6H), 1.36- 1.13 (m, 48H), 0.88 (t, J=6.7Hz, 6H).
Ae) (3,5- dimethyl -2- (2- methyl -4- oxo butyl- 2- yls) phenyl) adipic acid 1,3- is double (palm acyloxy) Propyl- 2- base esters (XXXV)
At 0 DEG C by PCC(PCC, 2.6mg, 12.2 μm of ol) adds alcohol XXXIV (5.4mg, 6.1 μm of ol) and C Salt (5mg) is in CH2Cl2In suspension in (0.5mL), the mixture is stirred at room temperature 1 hour.Filtered by short silicagel pad The reaction system, is eluted with 50% ethyl acetate/hexane, and be concentrated under reduced pressure filtrate.Thick aldehyde XXXV (5.4mg, quantitative) is obtained, is yellow Color grease, it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 9.53 (t, J=2.6Hz, 1H), 6.84 (d, J=1.4Hz, 1H), 6.57 (d, J =1.8Hz, 1H), 5.27 (m, 1H), 4.31 (dd, J=11.9,4.3Hz, 2H), 4.15 (dd, J=11.9,5.9Hz, 2H), 2.80 (d, J=2.6Hz, 2H), 2.57 (t, J=7.1Hz, 2H), 2.53 (s, 3H), 2.40 (t, J=7.0Hz, 2H), 2.31 (t, J=7.6Hz, 5H), 2.24 (s, 3H), 1.83-1.72 (m, 4H), 1.65-1.56 (m, 4H), 1.55 (s, 6H), 1.35- 1.16 (m, 48H), 0.88 (t, J=6.7Hz, 6H).
Af) 3- (2- ((6- ((double (palm acyloxy) the propyl- 2- yls of 1,3-) epoxide) -6- oxohexanoyls) epoxide) -4,6- 3,5-dimethylphenyl) -3 Methylbutanoic acid (XXXVI)
By liquor potassic permanganate (the 1 of 0.0775M：1 acetone/water solution, 200 μ L, 15.5 μm of ol) it is added in acetone In aldehyde XXXV (12.5mg, 0.0340 μm of ol) in (0.5mL) and water (0.1mL), the mixture is stirred at room temperature 18 hours. The reaction system is diluted with water (10mL), pH 2 is acidified to using 1M HCl, with ethyl acetate (3 × 15mL) aqueous layer extracted.With The organic extract that salt solution (30mL) washing merges, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.By silica gel chromatography Purifying (10%-20% ethyl acetate/hexanes), obtains sour XXXVI (9.5mg, 75%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 6.82 (d, J=1.3Hz, 1H), 6.56 (d, J=1.7Hz, 1H), 5.26 (m, 1H), 4.32 (dd, J=11.9,4.4Hz, 2H), 4.15 (dd, J=11.9,5.8Hz, 2H), 2.82 (s, 2H), 2.60 (t, J= 7.0Hz, 2H), 2.55 (s, 3H), 2.40 (t, J=6.9Hz, 2H), 2.31 (t, J=7.6Hz, 4H), 2.22 (s, 3H), 1.84- 1.72 (m, 4H), 1.66-1.49 (m, 4H), 1.58 (s, 6H), 1.36-1.19 (m, 48H), 0.88 (t, J=6.8Hz, 6H).
Ag) (2- (4- (((8R, 9S, 10R, 13S, 14S, 17S) -10,13- dimethyl -3- oxo -2,3,6,7,8,9, Tetrahydrochysene -1H- cyclopentano [a] phenanthrene -17- bases of 10,11,12,13-14,15,16,17- ten) epoxide) -2- methyl -4- oxo butyl- 2- Base) -3,5- 3,5-dimethylphenyls) double (palm acyloxy) propyl- 2- base esters (22) of adipic acid 1,3-
By 4- (dimethylamino) pyridine (DMAP, 1.8mg, 14.4 μm of ol), EDCHCl (6.9mg, 36.1 μm of ol) and testis Ketone (7.5mg, 26.0 μm of ol) adds acid XXXVI (13.0mg, 14.4 μm of ol) in CH2Cl2In solution in (1mL), this is mixed Thing is stirred at room temperature 26 hours.Use CH2Cl2(5mL) dilutes the reaction system, adds silica gel, and be concentrated under reduced pressure the mixture.Pass through Silica gel chromatography (15%-20% ethyl acetate/hexanes), obtains compound 22 (8.6mg, 51%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 6.80 (d, J=1.8Hz, 1H), 6.55 (d, J=1.7Hz, 1H), 5.72 (s, 1H), 5.27 (m, 1H), 4.45 (dd, J=9.1,7.3Hz, 1H), 4.31 (dd, J=11.9,4.4Hz, 2H), 4.15 (dd, J= 11.9,5.8Hz, 2H), 2.80 (ABq, 2H), 2.58 (t, J=7.0Hz, 2H), 2.54 (s, 3H), 2.48-2.23 (m, 10H), 2.21 (s, 3H), 2.11-1.97 (m, 2H), 1.86-1.47 (m, 16H), 1.55 (s, 6H), 1.43-1.19 (m, 49H), 1.17 (s, 3H), 1.12-0.82 (m, 4H), 0.88 (t, J=6.9Hz, 6H), 0.65 (s, 3H).
Ah) (2- (4- (((1S, 4S) -4- (3,4- dichlorophenyls) -1,2,3,4- tetrahydrochysenes-naphthalene -1- bases) (methyl) amino) - 2- methyl -4- oxo butyl- 2- yls) -3,5- 3,5-dimethylphenyls) double (palm acyloxy) propyl- 2- base esters (1) of adipic acid 1,3-
By 4- (dimethylamino) pyridine (DMAP, 0.9mg, 7.8 μm of ol), EDCHCl (4.4mg, 23.3 μm of ol), Et3N (5.0 μ L, 66.6 μm of ol) and sertraline hydrochloride (5.3mg, 15.5 μm of ol) add acid XXXVI (7.0mg, 7.8 μm of ol) in CH2Cl2 In solution in (0.5mL), the mixture is stirred at room temperature 16 hours.Use CH2Cl2(3mL) dilutes the reaction system, adds Silica gel, be concentrated under reduced pressure the mixture.By Silica gel chromatography (10%-20% ethyl acetate/hexanes), compound 1 is obtained (5.6mg, 61%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 7.32 (d, J=8.3Hz, 0.7H), 7.31 (d, J=8.3Hz, 0.3H), 7.25- 7.11 (m, 2H), 7.09-7.02 (m, 1.3H), 6.97-6.90 (m, 1H), 6.87-6.78 (m, 2.4H), 6.72 (dd, J= 8.3,2.0Hz, 0.3H), 6.58 (d, J=1.5Hz, 0.7H), 6.55 (d, J=1.5Hz, 0.3H), 5.88 (dd, J=10.7, 6.3Hz, 0.7H), 5.25 (m, 1H), 4.94 (dd, J=10.8,5.7Hz, 0.3H), 4.30 (dd, J=11.9,4.4Hz, 2H), 4.20-4.14 (m, 1H), 4.14 (dd, J=11.9,4.4Hz, 2H), 3.07 (d, J=15.4Hz, 0.7H), 3.00 (d, J= 4.9Hz, 0.6H), 2.82 (d, J=15.4Hz, 0.7H), 2.64 (s, 2.1H), 2.62-2.53 (m, 5.3H), 2.48 (t, J= 7.1Hz, 0.6H), 2.39 (t, J=7.1Hz, 1.4H), 2.31 (t, J=7.6Hz, 4.6H), 2.23 (s, 2.1H), 2.21 (s, 0.9H), 1.99-1.91 (m, 1H), 1.85-1.72 (m, 4H), 1.71-1.53 (m, 13H), 1.36-1.19 (m, 48H), 0.88 (t, J=6.9Hz, 6H).Note：Fraction integrate reflect exist rotational isomer~7：3 mixtures, this is attributed to limited Around the rotation of N- methyl nitrosoureas functional group.
The characterize data of the compound of the formula (I) comprising trimethyl lock of other examples is provided in table 5 below.
The representational compound of table 5.1H NMR datas
The method that embodiment 6. is used for the compound for preparing formula (I), wherein Y represent unsubstituted or short chain (n=2,3) α- Methyl or the alkyl of Beta-methyl substitution, and L represents that X'C (O), wherein X' are O.
Ai) two palmitic acid 2- ((the 4- bromines bytyry) epoxide) base esters of propyl- 1,3- bis- (XXIII)
By 4- (dimethylamino) pyridine (DMAP, 64.4mg, 0.527mmol) and N, N '-dicyclohexylcarbodiimide (DCC, 218mg, 1.05mmol) sequentially add 4- bromo-butyric acids (XXII) (141mg, 0.844mmol) and III (300mg, 0.527mmol) In CH2Cl2In solution in (12mL), the mixture is stirred at room temperature 19 hours.Use CH2Cl2It is mixed that (15mL) dilution is obtained Suspension, is cooled to 0 DEG C, is filtered by celite, then use CH2Cl2(20mL) is washed.With 1M HCl, water, saturated aqueous solution NaHCO3With Salt solution (each 30mL) washs organic phase, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.Carry out silica gel chromatography (5% acetic acid Ethyl ester/hexane), bromine triglycerides XXIII (352mg, 93%) is obtained, it is colorless solid.
1H NMR (400MHz, CDCl3) δ 5.27 (m, 1H), 4.32 (dd, J=12.0,4.2Hz, 2H), 4.14 (dd, J= 12.0,6.0Hz, 2H), 3.46 (t, J=6.5Hz, 2H), 2.53 (t, J=7.1Hz, 2H), 2.32 (t, J=7.6Hz, 4H), 2.20-2.15 (m, 2H), 1.65-1.58 (m, 4H), 1.36-1.21 (m, 48H), 0.88 (t, J=6.9Hz, 3H).
In some cases, wherein ω-halogenated carboxylic acid XXII be not it is commercially available, can be as described by using corresponding Lactone and then open loop are synthesized.
Aj) OMEGA-pentadecalactone (XXXVIII)
M- chlorine benzylhydroperoxide (m-CPBA, 70% is pure, 687mg, 2.79mmol) is added into cyclopentano decanone at 0 DEG C (500mg, 2.23mmol) is in CH2Cl2In solution in (6mL), the reaction system is stirred at room temperature 4 days and 22 hours.3 days The reaction system of the decile to obtaining afterwards1The ketone consumption rate of H NMR analyses display 74%, now, adds a part of m- CPBA(150mg).After 4 days and 22 hours, CH is used2Cl2(20mL) dilutes the reaction system, uses saturated aqueous solution NaHCO3(3× 20mL), water (20mL) and salt solution (20mL) are washed, and are concentrated under reduced pressure, and obtain crude product.Carry out silica gel chromatography (5%-10% second Acetoacetic ester/hexane), lactone XXXVIII (463mg, 86%) is obtained, it is colorless oil.
1H NMR (400MHz, CDCl3) δ 4.15-4.11 (m, 2H), 2.35-2.29 (m, 2H), 1.71-1.58 (m, 4H), 1.45-1.27 (m, 20H).
Ak) 15- iodine pentadecanoic acid (XXII)
Chlorine trimethyl silane (TMSCl, 242 μ L, 1.91mmol) is added into XXXVIII (153mg, 0.636mmol) and iodine Change in suspension of the sodium (286mg, 1.91mmol) in acetonitrile (1.5mL), the mixture is heated at reflux 21 hours.This is anti- System is answered to be cooled to room temperature, with water (10mL) and 10%Na2S2O3The aqueous solution (10mL) dilutes, and is extracted with ethyl acetate (3 × 20mL) Take.The organic extract for merging is washed with salt solution (40mL), (MgSO is dried4), it is concentrated under reduced pressure, obtain crude product.Carry out silica gel Chromatography (50% ethyl acetate/hexane), obtains acid iodide XXII (87.4mg, 37%, 70% is pure), is yellow oil.Observation To after chromatogram1The intensity of the several impurity signals in H NMR spectras increases, and one of doubtful two submembers are by hydrolysis Hydroxy acid (δ 3.53, hydroxyl that iodide functional group is formed；δ 3.18, iodine).
1H NMR (400MHz, CDCl3) δ 3.18 (t, J=7.1Hz, 2H), 2.34 (t, J=7.5Hz, 2H), 1.86-1.78 (m, 2H), 1.68-1.57 (m, 2H), 1.42-1.22 (m, 20H).
Al) 3- methyl tetrahydrochysene -2H- pyran-2-ones (XXXIX)
N-butyllithium solution (hexane solution of 1.0M, 5.49mL, 5.49mmol) is added drop-wise to diisopropylamine at 0 DEG C In the solution of (910 μ L, 6.49mmol) in THF (4mL), the mixture is stirred 30 minutes at 0 DEG C, obtain LDA faint yellow Solution, is then cooled to -40 DEG C.Cold (- 40 DEG C) δ-valerolactone (500mg, 4.99mmol) is added dropwise in THF by sleeve pipe Solution in (4mL), the mixture that will be obtained is stirred 10 minutes at -40 DEG C, is subsequently cooled to -78 DEG C.Then iodomethane is added dropwise (466 μ L, 7.49mmol), 0 DEG C is lentamente warmed to by the mixture, lasts 4 hours.By being slowly added acetic acid (320 μ L) Stop reaction, diluted with ethyl acetate (10mL) and water (15mL), with ethyl acetate (3 × 15mL) aqueous phase extracted.Use saturation NaHCO3The organic extract that the aqueous solution and salt solution (each 30mL) washing merge, dries (MgSO4), it is concentrated under reduced pressure, slightly produced Thing.Silica gel chromatography (contains 1%Et3The 15%-17.5% ethyl acetate/hexanes of N), obtain Alpha-Methyl-δ-valerolactone XXXIX (144mg, 25%), is colorless oil.
1H NMR (400MHz, CDCl3) δ 4.37-4.26 (m, 2H), 2.58 (ddt, J=11.1,7.0,7.0Hz, 1H), 2.09 (tt, J=12.4,6.2Hz, 1H), 1.98-1.83 (m, 2H), 1.54 (ddt, J=13.4,11.1,7.4Hz, 1H), 1.26 (d, J=6.9Hz, 3H).
Am) 4- methyl tetrahydrochysene -2H- pyran-2-ones (XL)
At 0 DEG C by the lithium methide (Et of 1.0M2O solution, 2.00mL, 2.00mmol) add CuI (190mg, 1.00mmol) In Et2In suspension in O (2mL), faint yellow reactant mixture is cooled to -40 DEG C at once.5,6- bis- is added dropwise by sleeve pipe Hydrogen -2H- pyran-2-ones (43.1 μ L, 0.50mmol) are in Et2Solution in O (2mL), 10 are stirred by the reaction system at -40 DEG C Minute, then stirred 10 minutes at 0 DEG C, it is stirred at room temperature 30 minutes.In -40 DEG C of yellow suspensions that will be obtained by syringe It is transferred to the saturation NH being stirred vigorously4In the mixture of the Cl aqueous solution (5mL) and ethyl acetate (5mL), the reaction system that will be quenched Lentamente warm to room temperature, last 30 minutes.The reaction system is diluted with water (5mL), is extracted with ethyl acetate (3 × 15mL), Use 1M Na2S2O3The organic extract merged with salt solution (each 30mL) washing, dries (MgSO4), be concentrated under reduced pressure, obtain thick β- Methyl-δ-valerolactone XL (22.7mg, 40%), is yellow oil, and it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 4.42 (ddd, J=11.4,4.9,4.0Hz, 1H), 4.27 (ddd, J=11.4, 10.6,3.8Hz, 1H), 2.68 (m, 1H), 2.17-2.06 (m, 2H), 1.92 (dqd, J=13.8,3.9,1.5Hz, 1H), 1.52 (m, 1H), 1.
An) (E) -6- (4- (allyloxy) -6- methoxyl group -7- methyl -3- oxo -1,3- dihydroisobenzofurans -5- Base) -4- methyl-hex- obtusilic acid allyl ester (XLI)
By -7- the alkene (DBU) of 1,8- diazabicyclos [5.4.0] 11 (602 μ L, 4.03mmol) and allyl bromide, bromoallylene (238 μ L, 2.82mmol) add Mycophenolic Acid (250mg, 0.809mmol) solution in DMF (15mL), by the mixture in room Temperature stirring 18 hours.The reaction system is diluted with ethyl acetate (20mL) and water (20mL), is extracted with ethyl acetate (2 × 30mL) Water phase.The organic extract for merging is washed with water and salt solution (each 40mL), (MgSO is dried4), it is concentrated under reduced pressure, obtain crude product. Silica gel chromatography (30% ethyl acetate/hexane) is carried out, allyl ester XLI (292mg, 93%) is obtained, is colorless oil.
1H NMR (400MHz, CDCl3) δ 6.09 (ddt, J=17.1,10.4,5.9Hz, 1H), 5.86 (ddt, J=17.2, 10.4,5.7Hz, 1H), 5.37 (dq, J=17.2,1.5Hz, 1H), 5.30-5.15 (m, 4H), 5.13 (s, 2H), 4.78 (dt, J =5.9,1.3Hz, 2H), 4.52 (dt, J=5.7,1.4Hz, 2H), 3.76 (s, 3H), 3.41 (d, J=6.5Hz, 2H), 2.44- 2.39 (m, 2H), 2.35-2.27 (m, 2H), 2.17 (s, 3H), 1.79 (s, 3H).
Ao) (E) -6- (4- (allyloxy) -6- methoxyl group -7- methyl -3- oxo -1,3- dihydroisobenzofurans -5- Base) -4- methyl hex- obtusilic acid (XLII)
By ester XLI (44.0mg, 0.110mmol) in 2M NaOH (330 μ L, 0.660mmol), water (1mL) and MeOH The mixture of (1.3mL) is stirred at room temperature 1.5 hours.The reaction system is acidified to pH 1 with 1M HCl, it is dilute with water (5mL) Release, then extracted with ethyl acetate (3 × 15mL).The organic extract for merging is washed with salt solution (30mL), (MgSO is dried4), It is concentrated under reduced pressure, obtain crude product.Carry out silica gel chromatography (40%-60% ethyl acetate/hexanes), obtain sour XLII (32.7mg, 83%), it is colorless oil.
1H NMR (400MHz, CDCl3) δ 6.09 (m, 1H), 5.36 (ddd, J=17.2,3.1,1.5Hz, 1H), 5.25- 5.16 (m, 2H), 5.13 (s, 2H), 4.77 (dt, J=5.9,1.3Hz, 2H), 3.76 (s, 3H), 3.42 (d, J=6.7Hz, 2H), 2.45-2.39 (m, 2H), 2.35-2.25 (m, 2H), 2.17 (s, 3H), 1.79 (s, 3H).
Ap) E)-two palmitic acid 2- ((4- ((6- (4- (allyloxy) -6- methoxyl group -7- methyl -3- oxo -1,3- dihydros Isobenzofuran -5- bases) -4- methyl hex- 4- enoyl-s) epoxide) bytyry) epoxide) base esters of propyl- 1,3- bis- (XLIII)
By -7- the alkene (DBU) of 1,8- diazabicyclos [5.4.0] 11 (18.5 μ L, 124 μm of ol) add XLII (30.6mg, 85.0 μm of ol) and suspensions of the bromide XXIII (55.5mg, 77.3 μm of ol) in toluene (2mL) in, by mixture backflow Heating 3.5 hours.The reaction system is cooled to room temperature, is acidified by adding 1M HCl (3-4 drops), diluted with water (10mL). With ethyl acetate (3 × 15mL) aqueous phase extracted, the organic extract for merging is washed with water and salt solution (each 30mL), dried (MgSO4), it is concentrated under reduced pressure, obtain crude product.Silica gel chromatography (15%-20% ethyl acetate/hexanes) is carried out, MPA is obtained sweet Three ester XLIII of oil (56.2mg, 73%), is colorless oil.
1H NMR (400MHz, CDCl3) δ 6.10 (ddt, J=17.2,10.4,5.9Hz, 1H), 5.37 (dq, J=17.2, 1.5Hz, 1H), 5.29-5.15 (m, 3H), 5.13 (s, 2H), 4.78 (dt, J=5.9,1.3Hz, 2H), 4.30 (dd, J= 11.9,4.4Hz, 2H), 4.14 (dd, J=11.9,5.8Hz, 2H), 4.06 (t, J=6.4Hz, 2H), 3.77 (s, 3H), 3.42 (d, J=6.8Hz, 2H), 2.41-2.35 (m, 4H), 2.34-2.25 (m, 6H), 2.18 (s, 3H), 1.97-1.88 (m, 2H), 1.79 (s, 3H), 1.65-1.52 (m, 4H), 1.35-1.19 (m, 48H), 0.88 (t, J=6.9Hz, 6H).
Aq) (E)-two palmitic acid 2- ((4- ((6- (4- hydroxyl -6- methoxyl group -7- methyl -3- oxo different benzene of -1,3- dihydros And furans -5- bases) -4- methyl hex- 4- enoyl-s) epoxide) bytyry) epoxide) base esters of propyl- 1,3- bis- (30)
By 1,3- dimethyl barbituric acids (12.4mg, 79.2 μm of ol) and Pd (PPh3)4(9.2mg, 7.92 μm of ol) are added in CH2Cl2Allyl ether XLIII (39.5mg, 39.6 μm of ol) in (3mL), the mixture is stirred 2 hours at 30 DEG C.This is anti- Answer mixture directly to go up short silicagel pad, eluted with ethyl acetate (40mL), be concentrated under reduced pressure filtrate, obtains crude product.Carry out silica gel Chromatography (15%-20% ethyl acetate/hexanes), obtains compound 30 (36.2mg, 96%), is colorless solid.
1H NMR (400MHz, CDCl3)(s, 1H), 5.30-5.21 (m, 2H), 5.20 (s, 2H), 4.30 (dd, J =11.9,4.4Hz, 2H), 4.14 (dd, J=11.9,5.8Hz, 2H), 4.06 (t, J=6.4Hz, 2H), 3.76 (s, 3H), 3.38 (d, J=7.0Hz, 2H), 2.43-2.35 (m, 4H), 2.34-2.27 (m, 6H), 2.15 (s, 3H), 1.97-1.89 (m, 2H), 1.80 (s, 3H), 1.65-1.52 (m, 4H), 1.34-1.21 (m, 48H), 0.87 (t, J=6.9Hz, 3H).
Ar) two palmitic acid 2- ((5- ((2- acetoxy benzoyls) epoxide) valeryl) epoxide) base esters of propyl- 1,3- bis- (8)
- 7- the alkene (DBU) (14.7mL, 98.4mmol) of 1,8- diazabicyclos [5.4.0] 11 is added into acetylsalicylic acid The suspension of (aspirin, 14.8mg, 81.9mmol) and bromide XXIII (40.0mg, 54.7mmol) in toluene (2mL) In, the mixture is heated at reflux 3.5 hours.The reaction system is cooled to room temperature, then with ethyl acetate (5mL) and water (15mL) dilutes.Separate aqueous layer, pH 2 is acidified to 1M HCl, is then extracted with ethyl acetate (3 × 20mL).With water and salt solution The organic extract that (each 40mL) washing merges, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.Carry out silica gel chromatography (10% ethyl acetate/hexane), obtains compound 8 (23.9mg, 53%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 8.01 (dd, J=7.9,1.6Hz, 1H), 7.56 (ddd, J=8.1,7.5, 1.7Hz, 1H), 7.31 (td, J=7.7,1.2Hz, 1H), 7.10 (dd, J=8.1,1.0Hz, 1H), 5.26 (m, 1H), 4.31 (dd, J=11.9,4.3Hz, 2H), 4.28 (t, J=6.9Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 2.40 (t, J =6.9Hz, 2H), 2.35 (s, 3H), 2.30 (t, J=7.6Hz, 4H), 1.83-1.74 (m, 4H), 1.64-1.54 (m, 4H), 1.35-1.19 (m, 48H), 0.88 (t, J=6.9Hz, 6H).
As) two palmitic acid 2- ((6- (((3R, 5R) -7- (2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- (phenylaminos Base formoxyl) -1H- pyrroles -1- bases) -3,5- dihydroxy heptyls acyl group) epoxide) caproyl) epoxide) base esters of propyl- 1,3- bis- (9) Synthesis
In the case of Atorvastatin (ATV), it is acetonide (isopropylidene that binary alcohol functional group needs masked Acetal), with the reaction for preventing its interference subsequent.Used at DBU and ω-bromo- TG XXIII in the toluene of backflow as described above Reason ATV acetonide XLIV, obtain protected prodrug XLV.Then dihydroxylic alcohols is exposed in acid condition, obtains compound 9。
As (i) 2- ((4R, 6R) -6- (2- (2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- (phenylcarbamoyls Base) -1H- pyrroles -1- bases) ethyl) -2,2- dimethyl -1,3- twoAlkane -4- bases) acetic acid (XLIV)
By p-methyl benzenesulfonic acid (p-TsOH, 10.1mg, 0.053mmol) be added in 2,2-dimethoxypropane (1.5mL) and In Atorvastatin (160mg, 0.265mmol) in acetone (1.5mL), the mixture is stirred at room temperature 15 hours.Use second Acetoacetic ester (30mL) dilutes the reaction system, and organic phase is washed with water (25mL) and salt solution (2 × 25mL), dries (MgSO4), subtract Pressure concentration, obtains crude product.By Silica gel chromatography (20%-30%-50% ethyl acetate/hexanes), acetonation is obtained Compound-acid XLIV (72.2mg, 46%), is colorless foam.
1H NMR (400MHz, CDCl3) δ 7.22-7.13 (m, 9H), 7.07 (d, J=7.7Hz, 2H), 7.03-6.97 (m, 3H), 6.86 (br s, 1H), 4.20 (m, 1H), 4.09 (m, 1H), 3.85 (m, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 2.54 (dd, J=15.8,6.8Hz, 1H), 2.43 (dd, J=15.8,5.6Hz, 1H), 1.71-1.61 (m, 2H), 1.53 (d, J= 7.1Hz, 6H), 1.38 (s, 3H), 1,36 (m, 1H), 1.34 (s, 3H), 1.09 (m, 1H).
As (ii) 2- ((6- (2- ((4R, 6R) -6- (2- (2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- (phenylaminos Base formoxyl) -1H- pyrroles -1- bases) ethyl) -2,2- dimethyl -1,3- twoAlkane -4- bases) acetoxyl group) caproyl) oxygen Base) -propyl- 1,3- diyls dipalmitate (XLV)
By -7- the alkene (DBU) of 1,8- diazabicyclos [5.4.0] 11 (4.3 μ L, 29.0 μm of ol) add acetonide - Sour XLIV (11.6mg, 19.3 μm of ol) and ω-solution of the bromo- TG XXIII (12.0mg, 16.1 μm of ol) in toluene (1.5mL) In, the mixture is heated at reflux 2.5 hours.The reaction system is cooled to room temperature, is diluted with ethyl acetate (30mL), use water (25mL), saturation NaHCO3The aqueous solution (25mL) and salt solution (25mL) washing organic phase, dry (MgSO4), it is concentrated under reduced pressure, obtain Crude product.Silica gel chromatography (20% ethyl acetate/hexane) is carried out, ATV- triglycerides XLV (13.0mg, 64%) is obtained, is Colorless oil.
1H NMR (400MHz, CDCl3) δ 7.23-7.12 (m, 9H), 7.06 (d, J=7.8Hz, 2H), 7.03-6.94 (m, 3H), 6.86 (br s, 1H), 5.25 (m, 1H), 4.30 (dd, J=11.9,4.4Hz, 2H), 4.19 (m, 1H), 4.14 (dd, J= 11.9,5.8Hz, 2H), 4.07 (m, 1H), 4.07 (t, J=6.6Hz, 2H), 3.82 (m, 1H), 3.70 (m, 1H), 3.57 (m, 1H), 2.48 (dd, J=15.7,7.0Hz, 1H), 2.36-2.27 (m, 7H), 1.70-1.58 (m, 10H), 1.53 (d, J= 7.1Hz, 6H), 1.36 (s, 3H), 1.29 (s, 3H), 1.44-1.20 (m, 51H), 1.05 (m, 1H), 0.88 (t, J=6.9Hz, 6H)。
The palmitic acid 2- of as (iii) two ((6- (((3R, 5R) -7- (2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- (benzene Base carbamoyl) -1H- pyrroles -1- bases) -3,5- dihydroxy heptyls acyl group) epoxide) caproyl) epoxide) base esters of propyl- 1,3- bis- (9)
P-methyl benzenesulfonic acid (1.6mg, 8.4mmol) is added into acetonide XLV (35.2mg, 27.9mmol) in CH2Cl2 In solution in (0.5mL) and MeOH (1mL), the reaction system is stirred at room temperature 5.5 hours.With the dilution reaction system CH2Cl2(20mL), uses saturation NaHCO3The aqueous solution (15mL) and salt solution (15mL) washing organic phase, dry (MgSO4), depressurize dense Contracting, obtains crude product.By Silica gel chromatography (20%-35% ethyl acetate/hexanes), obtain compound 9 (14.6mg, 43%), it is colorless oil.
1H NMR (400MHz, CDCl3) δ 7.22-7.13 (m, 9H), 7.06 (d, J=7.6Hz, 2H), 7.02-6.96 (m, 3H), 6.85 (br s, 1H), 5.25 (m, 1H), 4.30 (dd, J=11.9,4.4Hz, 2H), 4.16 (m, 1H), 4.14 (dd, J= 11.9,5.6Hz, 2H), 4.10 (t, J=7.5Hz, 2H), 4.10 (m, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.58 (m, 1H), 2.40 (d, J=6.1Hz, 2H), 2.33 (t, J=7.4Hz, 2H), 2.31 (t, J=7.6Hz, 4H), 1.73-1.51 (m, 10H), 1.54 (d, J=7.4Hz, 6H), 1.50-1.34 (m, 3H), 1.33-1.20 (m, 49H), 0.88 (t, J=6.9Hz, 1H)。
The compound of the formula (I) of other examples is provided in table 6 below, wherein L represents X'C (O).Table 6. formula (I's) has Representational compound1H NMR datas
The method that embodiment 7. is used for the compound for preparing formula (I), wherein Z represents C (O) R3, and R3Represent to hydroxybenzyl Carbonyl (PHB) suicidal group, and L represents that X', wherein X' are O, S or NR4。
Synthesis of the scheme 8. with the compound to the suicidal linker of hydroxybenzyl carbonyl
In order to synthesize comprising the prodrug to hydroxybenzyl (PHB) the suicidal group of carbonyl, first will be to hydroxy-benzyl alcohol (XLVI) primary hydroxyl protection is silyl ether, free phenolic hydroxyl group is coupled with acid-TG IV, obtains PHB triglycerides XLVIII.After removing silicon protection group, activation primary alconol XLIX can be processed by with p-nitrophenyl chloroformate ester (PNP), obtain PNP Carbonic ester L.By reacting displacement PNP groups in the basic conditions with pharmaceutically active agents (AX ' H), desired PHB prodrugs are obtained LI。
At) 4- (((t-butyldimethylsilyl) epoxide) methyl) phenol (XLVII)
By imidazoles (85.1mg, 1.25mmol) and the tert-butyl group (chlorine) dimethylsilane (TBSCl, 90.4mg, 0.600mmol) Add in solution of 4- hydroxy-benzyl alcohols (XLVI) (62.1mg, 0.500mmol) in DMF (4mL), the mixture is stirred in room temperature Mix 45 minutes.The reaction system is diluted with ethyl acetate (30mL), with water (30mL), saturation NaHCO3The aqueous solution (30mL) and salt Water (30mL) washs organic phase, dries (MgSO4), it is concentrated under reduced pressure, TBS ethers XLVII (119mg, quantitative) is obtained, it is colorless oil Thing, it is used without being further purified.
1H NMR (400MHz, CDCl3) δ 7.21-7.15 (m, 2H), 6.83-6.78 (m, 2H), 4.66 (s, 2H), 0.93 (s, 9H), 0.08 (s, 6H).
Au) 10- (4- (((t-butyldimethylsilyl) epoxide) methyl)-phenyl) decanedioic acid 1- (double (palms of 1,3- Acyloxy) propyl- 2- yls) ester (XLVIII)
By 4- (dimethylamino) pyridine (DMAP, 11.8mg, 0.0966mmol) and EDCHCl (46.3mg, Acid-TG IV (80.0mg, 0.106mmol) and phenol XLVII (23.0mg, 0.0966mmol) 0.241mmol) are added in CH2Cl2 In solution in (2.5mL), the mixture is stirred at room temperature 18 hours.Use CH2Cl2(10mL) dilutes the reaction system, adds Silica gel, be concentrated under reduced pressure the mixture.By Silica gel chromatography (5%-7.5%-10% ethyl acetate/hexanes), PHB is obtained Triglycerides XLVIII (60.7mg, 65%, 2 step), is colorless oil.
1H NMR (400MHz, CDCl3) δ 7.35-7.28 (m, 2H), 7.05-6.99 (m, 2H), 5.26 (m, 1H), 4.72 (s, 2H), 4.29 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 2.53 (t, J=7.5Hz, 2H), 2.32 (t, J=7.5Hz, 2H), 2.30 (t, J=7.5Hz, 4H), 1.78-1.70 (m, 2H), 1.67-1.55 (m, 6H), 1.43-1.20 (m, 56H), 0.93 (s, 9H), 0.87 (t, J=6.8Hz, 6H), 0.09 (s, 6H).
Av) 10- (4- (hydroxymethyl) phenyl) decanedioic acid 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) ester (XLIX)
10- camphorsulfonic acids (2.1mg, 8.91 μm of ol) are added in CH2Cl2TBS ethers in (0.8mL) and MeOH (0.8mL) In XLVIII (57.8mg, 59.4 μm of ol), the mixture is stirred at room temperature 2 hours.Use CH2Cl2(20mL) dilutes the reactant System, uses saturation NaHCO3The aqueous solution and salt solution (each 20mL) washing organic phase, dry (MgSO4), it is concentrated under reduced pressure, obtain crude product. By Silica gel chromatography (25%-35% ethyl acetate/hexanes), alcohol XLIX (46.9mg, 92%) is obtained, be colourless solid Body.
1H NMR (400MHz, CDCl3) δ 7.41-7.32 (m, 2H), 7.10-7.01 (m, 2H), 5.25 (m, 1H), 4.67 (s, 2H), 4.28 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 2.54 (t, J=7.5Hz, 2H), 2.31 (t, J=7.5Hz, 2H), 2.30 (t, J=7.5Hz, 4H), 1.89 (br s, 1H), 1.78-1.70 (m, 2H), 1.65-1.55 (m, 6H), 1.46-1.20 (m, 56H), 0.87 (t, J=6.9Hz, 6H).
Aw) 10- (4- ((((4-nitrophenoxy) carbonyl) epoxide) first-yl) benzene-yl) decanedioic acid 1- (double (palms of 1,3- Acyloxy) propyl- 2- yls) ester (L)
Chloro-carbonic acid 4- nitros phenyl ester (13.9mg, 69.1 μm of ol) and pyridine (7.8 μ L, 96.0 μ L) are added at 0 DEG C CH2Cl2In alcohol XLIX (33.0mg, 38.4 μm of ol) in (2mL), the mixture is stirred 20 minutes at 0 DEG C, then in room temperature Stirring 2.5 hours.Use CH2Cl2(20mL) dilutes the reaction system, uses saturation NaHCO3The aqueous solution and salt solution (each 20mL) are washed Organic phase, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.By Silica gel chromatography (10%-20% ethyl acetate/ Hexane), PNP carbonic esters L (38.7mg, 98%) is obtained, it is colorless solid.
1H NMR (400MHz, CDCl3) δ 8.30-8.23 (m, 2H), 7.49-7.43 (m, 2H), 7.41-7.35 (m, 2H), 7.15-7.09 (m, 2H), 5.28 (s, 2H), 5.26 (m, 1H), 4.30 (dd, J=11.9,4.3Hz, 2H), 4.15 (dd, J= 11.9,5.9Hz, 2H), 2.56 (t, J=7.5Hz, 2H), 2.32 (t, J=7.5Hz, 2H), 2.31 (t, J=7.5Hz, 4H), 1.79-1.71 (m, 2H), 1.66-1.55 (m, 6H), 1.45-1.20 (m, 56H), 0.87 (t, J=6.9Hz, 6H).
Ax) 10- (4- ((((((8R, 9S, 10R, 13S, 14S, 17S) -10,13- two-methyl -3- oxo -2,3,6,7,8, Tetrahydrochysene -1H- cyclopentanos [a] of 9,10,11,12,13,14,15,16,17- ten-phenanthrene -17- bases) epoxide) carbonyl) epoxide) methyl) benzene Base) decanedioic acid 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) ester (28)
By 4- (dimethylamino) pyridine (DMAP, 6.2mg, 50.8 μm of ol) and the DIPEA (CH of 0.16M2Cl2Solution, 80.0 μ L, 12.7 μm of ol) testosterone (11.7mg, 40.6 μm of ol) and PNP carbonic esters L (26.0mg, 25.4 μm of ol) are added in CH2Cl2 In solution in (0.8mL), the mixture is stirred at room temperature 4 days and 20 hours.Use CH2Cl2(20mL) dilutes the reactant System, uses saturation NaHCO3The aqueous solution and salt solution (each 2 × 15mL) are washed, and dry (MgSO4), it is concentrated under reduced pressure, obtain crude product.It is logical Silica gel chromatography (10%-20% ethyl acetate/hexanes) is crossed, compound 28 (9.8mg, 33%) is obtained, is colorless solid.
1H NMR (400MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.10-7.05 (m, 2H), 5.73 (s, 1H), 5.26 (m, 1H), 5.12 (s, 2H), 4.52 (dd, J=8.9,7.8Hz, 1H), 4.29 (dd, J=11.9,4.3Hz, 2H), 4.14 (dd, J=11.9,5.9Hz, 2H), 2.54 (t, J=7.5Hz, 2H), 2.47-2.17 (m, 11H), 2.02 (m, 1H), 1.89-1.81 (m, 2H), 1.78-1.54 (m, 12H), 1.47-1.19 (m, 59H), 1.18 (s, 3H), 1.10-0.93 (m, 4H), 0.87 (t, J =6.8Hz, 6H), 0.85 (s, 3H).
Ay) 10- (4- (((((1S, 4S) -4- (3,4- dichlorophenyls) -1,2,3,4- naphthane -1- bases) (methyl) amino Formoxyl) epoxide) methyl) phenyl) decanedioic acid 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) ester (6)
By 4- (dimethylamino) pyridine (DMAP, 6.3mg, 51.2 μm of ol) and the DIPEA (CH of 0.59M2Cl2Solution, 10.0 μ L, 5.9 μm of ol) sertraline hydrochloride (10.0mg, 29.3 μm of ol) and PNP carbonic esters L (15.0mg, 14.6 μm of ol) are added in CH2Cl2 In solution in (0.6mL), the mixture is stirred at room temperature 18 hours.Use CH2Cl2(25mL) dilutes the reaction system, with full And NaHCO3The aqueous solution (3 × 20mL) and salt solution (20mL) are washed, and dry (MgSO4), it is concentrated under reduced pressure, obtain crude product.By silicon Glue chromatography purifies (3%-6% ethyl acetate/toluene), obtains compound 6 (11.3mg, 65%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 7.46-7.28 (m, 3.5H), 7.25-7.16 (m, 2.5H), 7.12-7.02 (m, 3H), 6.95 (d, J=7.2Hz, 1H), 6.81 (m, 1H), 5.51 (m, 0.6H), 5.36 (m, 0.4H), 5.27 (m, 1H), 5.20 (s, 2H), 4.29 (dd, J=11.9,4.3Hz, 2H), 4.19 (m, 1H), 4.15 (dd, J=11.9,5.6Hz, 2H), 4.15 (dd, J=11.6,5.6Hz, 1H), 2.73 (s, 1.2H), 2.69 (s, 1.8H), 2.59-2.52 (m, 2H), 2.36-2.24 (m, 7H), 2.00 (m, 1H), 1.83-1.69 (m, 4H), 1.66-1.55 (m, 6H), 1.45-1.19 (m, 56H), 0.88 (t, J= 6.9Hz, 6H).Note：Fraction is integrated and reflects presence~3：2 rotamer mixture, this is attributed to limited around N- The rotation of methyl carbamate functional group.
The method that embodiment 8. is used for the compound for preparing formula (I), wherein Z represents C (O) R3, and R3Represent upset ester self The group of destruction, and L represents that X', wherein X' are O, S or N (R4)。
Scheme 9：The synthesis of the compound of the linker with upset ester self-destruction (FSI)
Suicidal (FSI) group of design upset ester, free drug activating agent is discharged with by being cyclized mechanism.Can be with Synthesis FSI prodrugs are coupled by making pharmaceutically active agents (A-X ' H) and 4- bromo-butyric acids (XXII), bromide LII is obtained.Use derivative Desired ester bond from the carboxylic acid ester interchange bromide LII generation target FSI prodrugs LIII of acid-TG IV.
Az) 4- bromo-butyric acids (8R, 9S, 10R, 13S, 14S, 17S) -10,13- dimethyl -3- oxo -2,3,6,7,8,9, 10,11,12,13,14,15,16,17- ten tetrahydrochysene -1H- cyclopentano [a] phenanthrene -17- base esters (LII)
4- (dimethylamino) pyridine (DMAP, 15.5mg, 0.130mmol) and DCC (43.8mg, 0.210mmol) are added Testosterone (29.9mg, 0.100mmol) and 4- bromo-butyric acids (XXII) (21.0mg, 0.130mmol) are in CH2Cl2Solution in (3mL) In, the mixture is stirred at room temperature 24 hours.0.6eq. acid, 1eq.DCC, 0.6eq.DMAP are added, the mixture is existed Room temperature is stirred for 2 days.Use CH2Cl2(10mL) dilutes the reaction system, adds silica gel, and be concentrated under reduced pressure the mixture.By silica gel Chromatography purifies (25% ethyl acetate/hexane), obtains bromide LII (26.7mg, 59%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 5.73 (s, 1H), 4.62 (dd, J=9.1,7.9Hz, 1H), 3.47 (t, J= 6.5Hz, 2H), 2.50 (td, J=7.1,1.0Hz, 2H), 2.47-2.23 (m, 4H), 2.22-2.13 (m, 3H), 2.06-1.99 (m, 1H), 1.85 (m, 1H), 1.78 (m, 1H), 1.74-1.63 (m, 2H), 1.61-1.53 (m, 2H), 1.52-1.32 (m, 3H), 1.23-1.15 (m, 1H), 1.19 (s, 3H) 1.11-0.91 (m, 3H), 0.83 (s, 3H).
Ba) 5- (4- (((8R, 9S, 10R, 13S, 14S, 17S) -10,13- dimethyl -3- oxo -2,3,6,7,8,9,10, Tetrahydrochysene -1H- cyclopentano [a] phenanthrene -17- bases of 11,12,13,14,15,16,17- ten) epoxide) -4- oxos butyl) 3- methylpents two Sour 1- (double (palm acyloxy) the propyl- 2- yls of 1,3-) ester (29)
- 7- the alkene (DBU) of 1,8- diazabicyclos [5.4.0] 11 (19 μ L, 125.7 μm of ol) is added into acid-TG IV (43.8mg, 62.9 μm of ol), bromide LII (27.5mg, 62.9 μm of ol) and tetrabutylammonium iodide (TBAI, 11.6mg, 31.4 μ Mol) in the suspension in toluene (3mL), the mixture is heated at reflux 6 hours.The reaction system is cooled to room temperature, so Diluted with ethyl acetate (10mL) and water (10mL) afterwards, with (3 × 10mL) ethyl acetate aqueous layer extracted.With water (20mL) and salt solution The organic extract that (20mL) washing merges, dries (MgSO4), it is concentrated under reduced pressure, obtain crude product.Carry out silica gel chromatography (15%-35% ethyl acetate/hexanes), obtains compound 29 (18.6mg, 28%), is colorless solid.
1H NMR (400MHz, CDCl3) δ 5.72 (s, 1H), 5.26 (m, 1H), 4.61 (dd, J=9.1,7.9Hz, 1H), 4.29 (ddd, J=11.9,4.3,1.6Hz, 2H), 4.12 (m, 4H), 2.50-2.12 (m, 16H), 2.03-1.92 (m, 3H), 1.84 (m, 1H), 1.77 (m, 1H), 1.74-1.54 (m, 8H), 1.53-1.32 (m, 2H), 1.31-1.21 (m, 49H), 1.18 (s, 3H), 1.16 (m, 1H), 1.10-1.01 (m, 2H), 1.02 (d, J=6.5Hz, 3H), 0.95 (m, 1H), 0.87 (t, J= 6.9Hz, 6H), 0.83 (s, 3H).
Lymphatic transport research in the rat of embodiment 8.
In order to confirm that heretofore described prodrug can promote to transport into lymph, studied in rats, wherein giving Mesenteric lymph duct is cannulated with being capable of continuous acquisition mesenteric lymph.Then by the lipid formulations comprising compound of interest Animal is applied to, lymph is gathered, then the drug concentration in lymph is quantified.
Prepare as described above compound of the invention or control compound with lipid as matrix preparation (Trevaskis, N.L. et al., Pharmaceutical Research, 2005,22 (11), 1863-1870).In short, by the chemical combination of about 2mg Thing (being 1mg in the case of compound 35 and compound 1), 40mg oleic acid and 25mg Tween 80s mix in vial, directly To balance (appropriate heating (being less than 50 DEG C) can be using short-term).Then will be by 5.6mL (PBSs (PBS, pH 7.4) The heated aqueous of composition in lipid phase (in the case of control compound, including Mycophenolic Acid, metoprolol tartrate, Ah Atorvastatin calcium, aspirin and sertraline hydrochloride, compound are each dissolved in PBS and non-lipid phase, for preparing comprising right According to the preparation of compound), it is described ultrasonically treated by emulsifying said preparation 2 minutes with ultrasonically treated machine is ultrasonically treated at room temperature Machine is provided with the 3.2 millimeters of miniature probe points run with 240 μm of amplitudes and 20kHz frequencies.Using in the whole preparations of HPLC-MS checkings Compound concentration.
Selection male Sprague-Dawley (SD) rats examine phenol for wheat for lymphatic transport research, wherein pharmaceutically active agents Sour (MPA), metoprolol (MET), Atorvastatin (ATV), Sertraline (SER) or celecoxib (CEL).Selection SD female is big It is the research of pharmaceutically active agents that mouse is used for wherein testosterone.This must eliminate the endogenous of relatively high and variable level in male rat Testosterone, it may interfere with quantifying for the testosterone of exogenous administration.Rat (240-320g) is maintained into standard diet and overnight fasting, Can free diversion, then tested.The rat of anesthesia is placed on heating cushion at 37 DEG C, (Edwards et al. as described above Advanced Drug Delivery Reviews2001,50 (1), 45-60) insert the cannula into duodenum and (applied for preparation With and rehydration), mesenteric lymph duct (being gathered for lymph) and arteria carotis (be used for take a blood sample).It is postoperative, by rat by with 2.8mL/h duodenums infusion physiological saline rehydration 0.5h.Lipid formulations are infused into duodenum 2h with 2.8mL/h, this Afterwards, infusion is changed into 2.8mL/h physiological saline, for remaining experiment.By lymph continuous acquisition 6-8h, into title in advance The Eppendorf tube comprising 10 μ L 1,000IU/mL heparin of weight.Change 1 collection tube per hour, surveyed by gravimetry Determine lymphoma likelesion.The aliquot of lymph sample hourly is stored in -80 DEG C, is then determined.
By the drug concentration in lymph be expressed as total medicine and including free drug and from different glyceride connect medicine. Determined by hydrolyzing lymph (discharging medicine with from the glyceride of any resterification), then evaluate free drug.
Product according to the concentration determined in the lymph volume and lymph of collection is calculated during gathering per hour and transported into pouring MPA, TST, MET, ATV, SER or CEL derivative of bar.Fig. 1 illustrates the intestines anaesthetized after intraduodenal infusion preparation 0-2h The lymphatic transport (% of institute's application dosage) of total testosterone related derivatives is accumulated in the female sd inbred rats of mesentery lymph cannula With the relation of time.Every kind of preparation includes the exemplary compounds or reference substance testosterone undecanoate (TU) of 2mg, their Monodisperseds in In 40mg oleic acid, 25mg Tween 80s and 5.6ml PBS.For the above-mentioned compound TU (n=4) described by Scriba et al. and change Data are expressed as average value ± SEM, wherein testosterone and glycerine three by compound 11 (n=3) and compound 10 and compound 14n=1 Ester units are coupled (compound 41, n=4) by butanedioic acid.Embedded figure represent rod diagram form endpoint data point (transport into The accumulation % dosage of lymph, lasts 8h).As from Fig. 1 and Biao 7 it will be apparent that exemplary compounds each significantly increase Strong testosterone is delivered to intestines lymph, about compares 7-9 times of TU.
The intraduodenal infusion of table 7. is to total compound (institute's application dosage after the rat of the mesenteric lymph cannula of anesthesia %) lymphatic transport (data are expressed as average value ± SEM, now n >=3).
Fig. 2 illustrates the male SD rat of the mesenteric lymph cannula anaesthetized after intraduodenal infusion preparation 0-2h The lymphatic transport (% of institute's application dosage) of middle compound of the accumulation comprising total MPA and the relation of time.Preparation is independent comprising 2mg Exemplary compound or MPA, their Monodisperseds are in 40mg oleic acid, 25mg Tween 80s and 5.6ml PBS.Data are represented It is average value ± SEM.Derive from the data of animal：N=5, MPA；N=3, compound 30, compound 34；N=6, compound 31；n =4, compound 32, compound 33 and compound 35.Embedded figure represents that the endpoint data point of rod diagram form (is transported into lymph Accumulation % dosage, last 8h).
Fig. 2 and the examples of Biao 8 compound of the invention significantly increase the lymphatic transport of MPA, increase compared with single MPA 43~132 times.Extend the transhipment that linker length enhances MPA, the lymphatic transport of MPA is improved administration by wherein compound 30 The 7.1% of dosage, and compound 34 is enhanced and is transported to 22.1%.Correlation between linker length and transhipment increase may It is attributed to monoglyceride intermediate and is easy to resterification, because alkyl chain is more long, is then more easily accessible to simulation because of natural glycerin three The monoglyceride that ester digestion is produced.Meaningfully, it is further observed that increase linker length is invalid, and applies compound 35 (wherein-Y-it is C20Alkyl) cause lymphatic transport to be less than to use (wherein-the Y-be C of compound 3414Alkyl) result that obtains.Just As that can find out from Fig. 3 and Biao 8, will not change what is obtained with the ester bond between thioesters alternative medicine activating agent and linker The lymph of compound turns (see, e.g. compound 31 and compound 40).
The lymph turn of the total compound in giving after being transfused in the rat preduodenal of the mesenteric lymph cannula of anesthesia of table 8. Fortune (% of institute's application dosage) (data are expressed as average value ± SEM).
As from Fig. 4, Figure 19 and Biao 9 it will be apparent that prevent ester to be connected to glyceride subunit with α or β methyl can To increase the tube chamber stability of compound and promote lymphatic transport.When compounds 10 corresponding with its straight chain or the phase of compound 13 Than when, α methyl branches in β methyl branches or compound 16 in compound 18 significantly stablize the mono-acid glycerine in gastro-intestinal Fluid Ester intermediate (referring to Figure 19).This causes that monoglyceride-simulation intermediate is more readily absorbed, and the ester again in enterocyte Change, therefore dramatically increased in lymph drug transport.
The lymph turn of the total compound in giving after being transfused in the rat preduodenal of the mesenteric lymph cannula of anesthesia of table 9. (data are expressed as average value ± SEM to fortune (% of institute's application dosage), now n >=3；Or average value ± scope, now n=2).
Similarly, there is methyl substituted TG simulation prodrug (connection alkyl spacer bases to glyceride skeleton in interval base α-or β -ester key) stability (Figure 23) of the MPA in GI chambers is improved, and cause tending to for the internal lymphatic transport of MPA More preferable trend (Fig. 5 and Biao 10).Fig. 5 and the examples of Biao 10 compound 36 (9.1%) and chemical combination compared with compound 31 (8.2%) The lymphatic transport of thing 38 (12.1%) improves, and compound 37 (12.6%) and compound 39 (28.4%) cause lymphatic transport point Gao Yu not compound 32 (9.6%) and compound 34 (22.1%).
The total MPA related derivatives in giving after being transfused in the rat preduodenal of the mesenteric lymph cannula of anesthesia of table 10. Lymphatic transport (% of institute's application dosage) (data are expressed as average value ± SEM).
When the compound phase ratio being conjugated with 1 ' (or 3 ') position or be connected by ehter bond, the present invention is in the position of triglycerides 2 ' The upper compound being conjugated by ester bond more effectively promotes lymphatic transport.
The data of the present inventor disclose out position and functional group's specificity is effective lympha targeted for MPA prodrugs For be important.In Fig. 6 and Biao 11, compound of the invention such as compound 30 and compound 32 successfully drench MPA Bar yield improves 43~60 times.Conversely, compound (wherein MPA is directly conjugated in 1 ' (or 3 ') position (compound of glycerol unit 42)), (wherein MPA- connections base section is conjugated to glycerol unit to compound by ehter bond, wherein the equivalent of-Y- is C4Alkyl (compound 43) or C6Alkyl (compound 44) or compound (wherein MPA is conjugated on 1 ' position of glycerol unit by ehter bond, And the equivalent of-Y- is C8Alkyl (compound 45) is bad substrate for lymphatic transport, cause lymphatic transport with it is independent MPA lymphatic transport be similar to.
Table 11. is to total MPA related derivatives after infusion in the rat preduodenal of the mesenteric lymph cannula of anesthesia Lymphatic transport (% of institute's application dosage) (data are expressed as average value ± SEM).
Fig. 7-11 and table 12 provide extra evidence, i.e. TG simulation prodrug strategies can extend to except MPA and testosterone with Outer compound.The lymph of total compound in after the rat ID infusions that the figure presents to the mesenteric lymph cannula of anesthesia Transhipment (% of dosage).The lymphatic transport of data display MET (Fig. 7), ATV (Fig. 8) and ASP (Fig. 9) is applying compound respectively 3rd, 9 and 8 it is improved afterwards.
Figure 10 provides the further evidence of the present invention, and medicine such as MPA and hydroxyl end of the example except carboxylic acid termination Outside the example of such as TST of medicine only, the lymph drug transport of such as medicine such as Sertraline (SER) that amine terminates can also lead to Cross be formed between medicine and glyceride the glyceride for being incorporated to suicidal linker simulation prodrug be improved.Figure 10 is presented To lymphatic transport (% of dosage) (tables of data of total compound in after the rat ID infusions of the mesenteric lymph cannula of anesthesia It is shown as being incorporated to the average value ± scope (n=of the compound 1 that trimethyl locks suicidal group and pharmaceutically active agents Sertraline 2) transhipment of total Sertraline derivative in lymph, is caused to be 41.0 ± 7.0%.Similarly, when compared with single medicine, Modification is with the group including p-hydroxybenzoate self-destruction group (compound 6) or the suicidal group of acetal and methyl Protection is closed with the ester bond (compound 7) of glyceride there is provided the enhancing in lymph drug transport.As another example, that is, wrap The trimethyl of the prodrug containing amine locks suicidal prodrug, the prodrug of nonsteroidal anti-inflammatory agent celecoxib (CEL, compound 5) Lymphatic transport is as shown in Figure 11.
Lymphatic transport of the table 12. to total medicine after infusion in the rat preduodenal of the mesenteric lymph cannula of anesthesia (% of institute's application dosage) (data are expressed as average value ± SEM, now n >=3；Or average value ± scope, now n=2).
Pharmacokinetics (PK) research in the rat of embodiment 9. and dog
In order to evaluate the oral administration biaavailability of compound of the invention, in rat and dog carrying out pharmacokinetics grinds Study carefully.In rat studies, anesthesia female (being used for testosterone correlative study) or male (being used for alfaxalone's correlative study) Sprague-Dawley rats (240-320g), and, then dispenser cannulated to arteria carotis.Then rat is made to recover consciousness simultaneously And overnight fasting, then start can free diversion experiment.Morning, by oral gavage using in lipid formulations Compound (except alfaxalone (ALP) and compound 2), the lipid formulations include the 1-2mg chemical combination being scattered in 2mL PBS (described to the lymphatic transport research in rat as described above, difference is only that small size for thing, 40mg oleic acid and 25mg Tween 80s PBS is used for conscious research herein).The oral formulations of ALP are fine comprising 1mL 0.5% (w/v) carboxymethyl in being suspended in salt solution The 7.5mg ALP of dimension element and 0.4% (v/v) Tween 80).The oral formulations of compound 2 include the 3mg being scattered in 1mL PBS Compound, 20mg oleic acid and 12.5mg Tween 80s.From using preceding 5min to 24h after administration blood sample is gathered from arteria carotis sleeve pipe simultaneously And 5min is centrifuged with separated plasma with 5000rpm.During blood specimen collection, rat after administration can free diversion at any time, but Fasting is kept again by 8 hours.Plasma sample is stored at -80 DEG C, is then determined by HPLC-MS-MS.In such case In, the free drug of determination sample (i.e. without the medicine of glyceride connection) and do not hydrolyze before the assay (because thus, making With lymph sample).Therefore the data reflect that drug transport enters lymph and then in body circulation from the medicine-glycerine of resterification Discharged in ester complexes.
In order to carry out the research of dog, female greyhound is maintained at least 5 days in big zooscopy facility, then start to grind Study carefully.Dog is adapted at least 4 days, then start this research.Make dog fasting 12h, untill 30min before dispenser.In order to be fed The research (n=4, TU or compound 13) of food state, dog receives normal business dog foods of the 680g comprising 5% fat 30 minutes, so Dispenser afterwards.In the research of fasting (n=1, compound 13), dog keeps fasting, after the 4h after administration untill.In this research Can freely be fetched water for whole dogs from start to finish.This study on the day of, No. 20 intravenous catheters are inserted into cephalic veins With blood-sample withdrawal.Make dog free movement after cannulated (without constraint).In order to carry out the research of as fed, dog An Teer is given (Andriol Testocaps) (commercialization TU products) or compound 13.An Teer is by Merck Sharp＆Dohme (the big profits of Australia It is sub-) Pty Limited provide and are configured to soft capsule, and it is sweet in propane diols mono laurate that it includes 12.0% (w/w) TU Grease (lauroglycol) FCC/ castor oil [40：60% (w/w)] in solution, wherein single Capsules group turn into 40mg TU, Propane diols glyceryl monolaurate FCC, castor oil, gelatin, glycerine and sunset yellow (E110).Compound 13 is prepared into based on length The self-emulsifying delivery system (SEDDS) of chain lipid, its by 30.5%w/w soybean oils, 30.5%w/w Maisine 35-1, 31.6%w/w Cremophor EL and 7.4%w/w ethanol are constituted.Preparation is packed into hard shell capsules.By the peace comprising 80mg TU 2 capsules of Te Er are 2 capsules of the compound 13 for being dissolved in 2g SEDDS preparations of 90mg compounds 13 comprising accumulated dose The greyhound of feeding is applied to, retropharynx is placed in as much as possible by by the capsule, is closed oral cavity and the throat that rubs is to stimulate Swallow to carry out.Then, by syringe oral administration 50mL water.Also the dog to fasting applies the preparation use of 2 granulation compounds 13 In fasting state research.It is (each by cephalic vein sleeve pipe blood sampling from preceding 5min to 10 hours after administration is applied after oral administration From about 3mL).Opening by flowing through heparinized saline (1-2IU/mL) the maintenance conduit of small size after blood sample is extracted every time Property.Blood sample during 24h is taken by venipuncture.Each it is transferred to by centrifugal separation plasma and by the aliquot of plasma sample Eppendorf tube, and be stored at -80 DEG C, then analyzed by LC-MS-MS.
Female sd inbred rats oral gavage preparation post dose normalization testosterone of Figure 12 examples to conscious arteria carotis intubation PC.Preparation includes 1mg TU or 2mg compounds of the invention, and they include and are scattered in 40mg oleic acid, 25mg tweens Testosterone in 80 and 2ml PBS.By the testosterone of Dose Calibration to 2mg/kg equivalent dosage.For whole groups (for each group, N=4 or 3), data display is average value ± SEM.Embedded figure is the dosage normalization blood plasma of the testosterone of rod diagram form AUC0-24hThe schematic diagram of (nmol × h/L).
The present invention is with more than C5Linker length compound cause apply rear testosterone systemic exposure (oral bio Availability) substantially increase.This is shown by Figure 12 and Biao 13, although wherein all 4 kinds of lymphatic transports of compound are similar to, Oral administration compound 11, compound 13 or after compound 14 parent testosterone systemic exposure be more than compound 41 or compound 10 Using latter 10- times (dosage normalization testosterone plasma A UC0-24h) (and higher than obtain TU~12-27 times) (referring to Fig. 1 and Biao 7).In this case, it is crucial for the obvious degree of linker more long and enhanced insoluble drug release.
Table 13. to conscious arteria carotis intubation SD female rats oral administrations described in pharmacokinetics after compound Parameter (by Dose Calibration to 2mg/kg equivalents testosterone dosages and data are expressed as average value ± SEM).
Purposes of the compound of the invention in testosterone systemic exposure is promoted also in different animals, in dog is confirmed. This is shown by Figure 13 and Biao 14.Data with rat are consistent, the systemic exposure of parent testosterone after oral administration compound 13 Significantly greater than (about 8 times, dosage normalization testosterone plasma A UC0-24h) are using the systemic exposure obtained after TU.Note, compound 13 exposed increases are not obviously influenceed by with food common use.
Table 14. is to the pharmacokinetic parameter after the greyhound oral administration testosterone prodrug of conscious feeding or fasting state (by Dose Calibration to 2mg/kg equivalents testosterone dosages).Data are expressed as average value ± SEM：TU (n=4) and (n of compound 13 =4), in as fed；And n=1, compound 13, in fasting state.
With with the ester bond of the glyceride protected by α or β methyl compound increase long-chain analog testosterone it is oral Bioavilability.
As from Fig. 4 and Biao 9 it will be apparent that methyl branch TG simulation prodrug be conducive to testis by stablizing MG intermediates The lymphatic transport of ketone.However, methyl modification is likely to reduce parent testosterone from the systematicness release in prodrugs.As Figure 14 Shown in table 15, for example, after compound 18 is applied, the systemic exposure of testosterone is less than its straight chain correspondence compounds in blood plasma 10, but, the lymphatic transport of compound 18 is about more than 2 times (referring to table 9).
In order to improve lymphatic transport and also allow whole body testosterone to discharge, it was found by the inventors that methyl substitution with it is more long The combination of alkyl chain length weakens the exposure observed for the compound with α or β methyl and reduces.Can be from Figure 14 and Biao 15 In find out, if-Y-increase to C after methyl modification8Alkyl, then when comparing with straight chain (compound 13), dissociate testis in blood plasma It is similar to when the release of ketone is for the analog that β methylates, and release obviously postpones to a certain extent, so as to provide Potential extension release.
Table 15. is to the pharmacokinetic parameter after the SD female rats oral administration compounds of conscious arteria carotis intubation (by Dose Calibration to 2mg/kg equivalents testosterone dosages and data are expressed as average value ± SEM).
The compound that suicidal group is incorporated between pharmaceutically active agents and linker is conducive to parent drug complete Discharged in body system, to reach the oral administration biaavailability of the compound connected higher than ester.
As finding out in Figure 15 and Biao 16, (there is trimethyl lock certainly in oral administration compound 22 and compound 26 The group that I destroys) after, systemic exposure of the testosterone in blood plasma is higher than respectively using compound 11 and compound 13 (without certainly The equivalent compound of the linker that I destroys, and it is that advance optimum performance performs one of prodrug to obtain compound 13) after obtain As a result.When comparing with TU, the plasma A UC of testosterone is approximately higher than using 40 times after compound 22, and is approximately higher than and is applied compound 90 times after 26.Similarly, addition trimethyl locks testosterone prodrug that suicidal group protects to Beta-methyl (wherein lymphatic transport High (Fig. 4), but systematicness release is not exclusively (Figure 15)) cause systemic exposure substantially to increase for compound 25 and 27 (to be approximately higher than TU 60-100 times).
Table 16. to conscious arteria carotis intubation SD female rats oral administrations described in pharmacokinetics after compound Parameter (by Dose Calibration to 2mg/kg equivalents testosterone dosages and data are expressed as average value ± SEM, now n >=3；Or it is average Value ± scope, now n=2).
It is further obvious that it is not the only effective suicidal group that trimethyl locks suicidal group, and As other example class effectively.For example, in Figure 16 and Biao 17, compound 21 (having the suicidal group of acetal) causes Whole body testosterone levels are higher than compound 11.It is this when the C5 prodrugs that the suicidal group of acetal is protected to β methyl are added Effect or even more notable (compound 23 compares with compound 18), wherein when comparing with TU, suicidal analog is led Causing the systemic exposure of testosterone increases by 90 times.
Table 17. to conscious arteria carotis intubation SD female rats oral administrations described in pharmacokinetics after compound Parameter (by Dose Calibration to 2mg/kg equivalents testosterone dosages and data are expressed as average value ± SEM).
In another example of the potentially beneficial property of suicidal group, the data in Figure 17 and Biao 18 are provided turns over The purposes evidence of the suicidal group of transesterification (FSI).The data display of compound 29, when with straight chain prodrug (compound 10) and When the compound (compound 18) of β methyl protection compares, after upset ester group insertion C5 β methyltestosterone prodrugs cause oral administration Whole body testosterone levels are dramatically increased.When comparing with TU, add to the suicidal group (chemical combination of hydroxybenzyl carbonyl (PHB) Thing 28) also cause testosterone to expose increase, but validity is less than other suicidal groups.
Table 18. to conscious arteria carotis intubation SD female rats oral administrations described in pharmacokinetics after compound Parameter (by Dose Calibration to 2mg/kg equivalents testosterone dosages and data are expressed as average value ± SEM).
Further it is clear that compound of the invention can promote the systemic exposure of the medicine of non-testosterone, such as Ah method Salon (ALP), i.e., another medicine (Figure 18 and Biao 19) with first pass effect high.Figure 18 examples are inserted to conscious arteria carotis ALP PCs after the male SD rat oral gavage preparation of pipe.Preparation includes 1mL 0.5% (w/v) the carboxylic first in salt solution 7.5mg ALP in base cellulose and 0.4% (v/v) Tween 80 are scattered in 20mg oleic acid, 12.5mg Tween 80s and 1ml PBS In 3mg compounds 2.Data display is average value ± SEM (for 2 groups of compound (n=4)；And n=1, for controlization Compound ALP groups).After ALP in oral administration suspension formulations, PC is extremely low (less than quantization limitation (LOD, 10ng/ ML)), most probable reason is the excessive first-pass metabolisms of ALP.Data are shown as qualitative instruction in figure 18, that is, obtain them low In the quantization limitation for determining.Conversely, when comparing with control compound ALP, compound 2 causes the systemic exposure of ALP (oral raw Thing availability) apparently substantially increase, but, the quantitative comparison of relative bioavailability is impossible, and this is attributed to ALP applies the extremely low exposures of rear ALP.
Table 19. to conscious arteria carotis intubation SD male rat oral administrations described in after compound the medicine of ALP move Mechanics parameter is (by Dose Calibration to 25mg/kg, ALP groups；And 4mg/kg equivalent ALP, 2 groups of compound).Data are expressed as Average value ± SEM：2 groups of compound (n=4)；N=1, ALP group.
Compound ira vitro hydrolysis caused by the rat digestive fluid of embodiment 10. or pig pancreatic lipases
Extracorporeal hydrolysis are carried out to MPA related compounds by being incubated together with rat digestive fluid.Rat digestion secretion Liquid gives conventional bile-ductus pancreaticus cannulated collection at once by before conduit enters duodenum (i.e. less than pancreatic secretion inlet point) From anesthetized rat.This can simultaneously gather bile and pancreatic juice.By digestive fluid continuous acquisition 2h, during this period, by blank fat Matter preparation (prepared as described in the research of rat lymphatic transport, but without medicine) 12 fingers are entered with the rate infusion of 2.8ml/h Intestines, to simulate the situation after dispenser.Bile and pancreatic juice are maintained 37 DEG C and 11 in collection 0.5h, for external prodrug Hydrolysising experiment.By the way that 0.375mL rats digestive fluid and 0.625ml to be carried the lipid formulations of medicine, (such as rat lymphatic transport grinds Prepared described in studying carefully) experiment that is hydrolyzed (at 37 DEG C) is incubated together.The volume ratio model bile of digestive fluid and preparation and In the flow velocity (~1.5mL/h) and internal lymphatic transport research process of pancreatic juice in duodenum preparation infusion rates (2.8mL/ h).10 μ L aliquots (in the sample that 0,2,5,10,15,30,60,90,120,180min take) are added into 990 μ L acetonitriles：Water (4：1, v/v) to terminate steatolysis in, vortex 1min and it is centrifuged 5 minutes with 4500g, with precipitating proteins, is then analyzed.Pass through HPLC-MS analyzes the residual compounds concentration of supernatant, and the potential product that analysis of compounds is hydrolyzed.
In order to provide compared with high throughput experiment, unless otherwise described, otherwise carried out by being incubated together with porcine pancreatic lipase The extracorporeal hydrolysis of TST related compounds.This provides the more reproducible source of pancreatin, is conducive to improving the circulation tested, And also be the challenge (because enzymatic activity in rat intestinal juice low) bigger than the rat enzyme for gathering.In short, in hydrolysising experiment Before, by the way that 1g pig pancreatin is scattered in into 5ml steatolysis buffer solution and 16.9 μ l 5M NaOH in prepare pancreatic lipase solution.This is mixed Suspension is sufficiently mixed and is centrifuged 15 minutes with 3500rpm at 5 DEG C, obtains supernatant.Adjusted to pH's 6.5 with NaOH Tri--maleates of 0.474g (2mM), 0.206g CaCl2.H2O (1.4mM) and 8.775g NaCl (150mM) prepares 1000ml amounts Steatolysis buffer solution.In order to evaluate the potential that prodrug is hydrolyzed in intestines, by drug solns (1mg/ml is dissolved in acetonitrile), 900 μ before 20 μ l L simulation intestines micellar solution [is buffered with 0.783g NaTDC (3mM) and 0.291g phosphatldylcholines (0.75mM) in 500ml steatolysis In liquid prepare] and 100 μ l enzyme solutions incubated at 37 DEG C.Take within 0,5,10,15,30,60,90,120 and 180 minutes after incubation The sample of 20 μ l Incubation solutions, and add in 180 μ l ACN terminating steatolysis.Be vortexed the mixture and with 5000rpm from The heart 5 minutes, with precipitating proteins, then analyzes.The residual compounds concentration of supernatant is analyzed by HPLC-MS, and is analyzed The potential product of compound hydrolysis.
When being incubated together with digestive ferment, the monoglyceride form of prodrug is extremely quickly formed.In simulation intestines condition Stability therefore preferably evaluated according to the stability of monoglyceride form generated by intestinal digestion process.Mono-acid Glyceride form must keep intactly being absorbed and in intestines compared to middle resterification, subsequently into lymph.(the n=of compound 10 3) with the monoglyceride form of compound 18 (n=1) and compound 13 (n=3) and compound 16 (n=3) in vitro with newly The rat bile and pancreatic juice (BPF) (compound 10 and 18) or porcine pancreatic lipase (compound 13 and 16) of fresh collection were incubated together Stability features in journey are displayed on α or β carbon the stability (figure for significantly increasing monoglyceride intermediate comprising methyl 19).When comparing with compound 10, this turns with the height lymph of compound 16 in the lymphatic transport increase of compound 18 and Fig. 4 Fortune is consistent.
Figure 20-22 provides methyl substitution includes the prodrug comprising suicidal linker to improve testosterone prodrug Other evidences of chamber stability, wherein suicidal group expection can reduce chamber stability.For example, in fig. 20, chemical combination The monoglyceride form of thing 11 or compound 13 is not highly stable during steatolysis is tested in vitro, and this locks for three-methyl It is similar or worse for suicidal analog (compound 22 and compound 26).Conversely, methyl substituted mono-acid is sweet Grease (compound 25 and compound 27) is substantially in vitro stabilization in hydrolytic attack and causes testosterone to expose to increase (Figure 15).
In figure 21, for the suicidal prodrug of acetal, similar comparing is it is clear that wherein compound 21 The chamber stability of (carrying suicidal linker) is less than compound 11, and compound 24 has the stabilization differed from than compound 13 Property.The combination of the acetal self-destruction group+β methyl protection in compound 23 causes chamber stability (Figure 21) and in vivo exposure (Figure 16) is significantly increased.
For overturning to suicidal group, the insertion methyl substituted combinations of self-destruction group+β (compound 29) is led Cause chamber stability increases (Figure 22) and the exposure of internal testosterone significantly than the straight chain homologue (compound 10) without self-destruction group Increase (Figure 17).
Similarly, compound 31 (n=5), compound 32 (n=4), compound 34 (n=1), compound 36 (n=2), change The monoglyceride form of compound 37 (n=1), compound 38 (n=1) and compound 39 (n=1) in vitro with fresh collection Rat bile and pancreatic juice (BPF) stability features comparative example together in incubation period retouching for MPA derivatives in Figure 23 In stating.Data are expressed as average value ± SEM, now n >=3；Or average value ± scope, now n=2.
When comparing with straight chain homologue, (alkyl to glycerine is connected with methyl substituted compound is carried in linker α-or β the -ester key of ester skeleton) degraded of the monoglyceride intermediate in stomach and intestine (GI) chamber is effectively reduced, cause in vivo Lymphatic transport increases.
Compound 36 and compound 38 and compound 31, compound 37 and compound 32 and compound 39 and compound 34 The degradation characteristic of monoglyceride digestion product relatively disclose significant difference in terms of stability.Prodrug is in GI chambers Optimizing stability also results in preferably lymphatic transport trend in vivo.Fig. 5 and Biao 10 display compound 36 (9.1%) or compound 38 (12.1%) lymphatic transport is better than compound 31 (8.2%)；Compound 37 (12.6%) causes transhipment higher than compound 32 (9.6%)；And compound 39 (28.4%) causes transhipment higher than compound 34 (22.1%).
Data also demonstrate monoglyceride (MG) intermediate (such as compound 31 and change of the prodrug comprising straight chain linker Compound 32) degraded in BPF is relatively rapid.It is probably the unstability of these MG intermediates because by for example single acyl of hydrolase Base glycerol lipase and pancreatic lipase are decomposed and caused.Therefore this reduce the drug conjugate that is absorbed and be utilized by resterification The availability of MG- sample intermediates.Finally, the lymphatic transport of medicine is which reduced.Prevent MG intermediate degradations therefore can strengthen Lymph drug transport.This (can be for example incorporated to the substitution of α or β methyl) or be realized by common use enzyme inhibitor in structure, For example, the data display in Figure 24 and Biao 20, suppresses by with monoacylglycerol lipase inhibitor (JZL184) and pancreatic lipase Agent (orlistat) common use, the lymphatic transport of the dosage of compound 32 increases to 18.8% (p from 9.6%<0.05).
Lymphatic transport of the table 20. to total compound after infusion in the rat preduodenal of the mesenteric lymph cannula of anesthesia (% of institute's application dosage) (data are expressed as average value ± SEM).
Unless required otherwise in context, otherwise through the word "comprising" in this specification and claims below For example " contain " with version or " including " be appreciated that and mean comprising described integer or integer group or step group, but It is not excluded for any other integer or integer group.
Any first publication (or from its information) being related in this specification or known any content are not Be considered as and be not construed as recognizing or allow or it is any type of imply first publication (or from its information) or Contents known constitutes the common knowledge in the field that the application is endeavoured.

Claims (23)

1. the compound of formula (I), or its pharmaceutically acceptable salt：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, alkenyl Or one or more carbon atoms in alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Aromatics or fat Race's heterocyclic group is substituted, and condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
Represent the residue of pharmaceutically active agents；
- L- be-X '-or-X ' C (O)-；
X ' is O, S, N, N (R4) or S (O)2NH；
Singly-bound is represented, now X ' is O, S, N (R4) or S (O)2NH；Or
Two single keys are represented, now X ' is N；
- Z- is-C (O)-or-C (O) R3-, now-L- be-X '-；Or
- Z- does not exist, now-L- be-X ' C (O)-；
R3It is suicidal group；And
R4It is H or C1-C4Alkyl.
2. compound according to claim 1, wherein R3It is selected from：
3. the compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, formula (II) table Show：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, alkenyl Or one or more carbon atoms in alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Aromatics or fat Race's heterocyclic group is substituted, and condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
Represent the residue of pharmaceutically active agents；
- L- be-X '-or-X ' C (O)-；
X ' is O, S or N (R4)；
R4It is H or C1-C4Alkyl；And
- Z- be-C (O)-, now-L- be-X '-；Or
- Z- does not exist, now-L- be-X ' C (O)-.
4., according to the compound of any one of claims 1 to 3, wherein Y and Z is chosen so as to promote the pharmaceutically active agents stabilization to turn It is transported to intestines lymph.
5. compound according to claim 4, wherein Y and Z is chosen so as to promote the pharmaceutically active agents thin in lymph, lymph Discharged in born of the same parents, lymphoid tissue, the tissue with higher fatty acid enzymatic activity such as adipose tissue, tumour, liver or body circulation.
6., according to the compound of any one of claim 1 to 5, it is expressed as formula (III)：
Wherein
R1、R2、-X-、There is the implication defined in claim 1 with-Z-；
R5And R6It each is selected from hydrogen and C1-C4Alkyl；And
N is 1 to 18；Or
Its pharmaceutically acceptable salt.
7. according to the compound of any one of claim 1 to 6, wherein the pharmaceutically active agents are to be shown after oral administration greatly The pharmaceutically active agents of the first-pass metabolism in 50% or the first-pass metabolism with alterable height.
8. according to the compound of any one of claim 1 to 7, wherein the pharmaceutically active agents be selected from testosterone, Mycophenolic Acid, it is female swash Plain (estrogen), morphine, metoprolol, Raloxifene, alfaxalone, statins for example Atorvastatin, buprenorphine, The different mountain of pentazocine, Propranolol, L-DOPA, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, nitric acid Pear ester, oxprenolol, labetalol, Verapamil, salbutamol, epithioandrostanol, melphalan or Lovastatin.
9. compound according to claim 8, wherein the pharmaceutically active agents are testosterones, and the compound is expressed as formula (IV)：
Wherein R1、R2There is the implication defined in claim 1 with X；
R5And R6It each is selected from hydrogen and C1-C4Alkyl；
- Z- is-C (O)-or-C (O) R3-；
R3It is suicidal group；And
N is 1 to 18；Or
Its pharmaceutically acceptable salt.
10. according to the compound of any one of claim 6 to 9, wherein R5It is methyl, and R6It is hydrogen.
11. according to the compound of any one of claim 6 to 9, wherein R5It is hydrogen, and R6It is methyl.
12. according to the compound of any one of claim 1 to 11, and wherein X and X ' is oxygen.
13. according to the compound of any one of claim 1 to 12, wherein R1And R2It is the residue of palmitic acid.
14. treatments or the method for prevention disease or obstacle, the increase of testosterone levels is beneficial in the disease or obstacle, is somebody's turn to do Method includes applying subject in need the compound according to any one of claim 9 to 13 of therapeutically effective amount.
15. methods according to claim 14, wherein the disease or obstacle be hypogonadism, because marrow failure causes Anaemia, because anaemia caused by kidney failure, chronic respiratory failure, chronic heart failure, steroid-dependent autoimmune disease, AIDS consumption, HAE or nettle rash, advanced breast cancer or menopause.
16. promote pharmaceutically active agents lymphatic transports and systematicness release method, its prodrug residue for including making formula (VI) or Its pharmaceutically acceptable salt is conjugated with the medical compounds：
Wherein
R1And R2Independently represent H or C2-C28The residue of aliphatic acid；
- X- is selected from-O- ,-NH- and-S-；
- Y- represents optionally substituted-C3-C20Alkyl-,-C3-C20Alkenyl-or-C3-C20Alkynyl-, wherein the alkyl, alkenyl Or one or more carbon atoms in alkynyl can be by NH, S, O, C5-C8Aromatics or aliphatic cyclic group or C5-C8Aromatics or fat Race's heterocyclic group is substituted, and condition is the alkyl, alkenyl or alkynyl no more than equivalent to straight chain C20The length of alkyl；
- Z- be-C (O)-,-C (O) R3- or-CH2-；
R3It is suicidal group；And
Represent the point that linker is conjugated with the pharmaceutically active agents.
17. methods according to claim 16, wherein R3It is selected from：
18. according to the method for any one of claim 14 to 17, wherein by the compound together with food oral administration promoting Enter to be transported to intestines lymph.
19. according to the method for any one of claim 14 to 18, wherein the compound is total to the preparation with lipid as matrix With oral administration promoting to be transported to intestines lymph.
20. according to the method for any one of claim 14 to 17, wherein by the compound and the common oral administration of enzyme inhibitor.
21. according to the compound of any one of claim 1 to 6, wherein the compound is chosen so as to promote the pharmaceutical activity Agent targeted delivery in lymphatic system.
22. compounds according to claim 21, wherein the pharmaceutically active agents be selected from nonsteroidal anti-inflammatory agent (NSAIDS, for example Aspirin, brufen, naproxen), cox 2 inhibitor (such as celecoxib, rofecoxib), corticosteroid anti-inflammatory agent (such as prednisolone, dexamethasone), antimalarial (such as HCQ), endoxan, nitrosoureas, platinum, methotrexate (MTX), sulphur Azoles purine, mercaptopurine, fluorouracil, actinomycin D, anthracycline (such as daunorubicin), mitomycin C, bleomycin, radiance Mycin, act on suppression exempt from the medicine (such as cyclosporine, tacrolimus, sirolimus) of albumen, SASP, leflunomide, Mycophenolate, opioid, FTY720, myriocin, Chlorambucil, Doxorubicin, nelarabine, cortisone, Sai meter Song, metacortandracin, Pralatrexate, vincaleukoblastinum, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, Ah Sugared cytidine, Dasatinib, imatinib mesylate, hydrochloric acid Ponatinib, vincristine sulphate, bendamustine hydrochloride, phosphoric acid Fludarabine, SKI-606, AMN107, U.S. amber his pungent, Anastrozole, capecitabine, Letrozole, taxol, gemcitabine, Fulvestrant, TAM, Lapatinib, Toremifene, Ipsapirone, Ai Libulin, albendazole, ivermectin, ethamine Piperazine, albendazole, Doxycycline, closantel, MVC, T-20, deoxythymidine, Zidovudine, department Ta Fuding, Didanosine, zalcitabine, Abacavir, Lamivudine, emtricitabine, tenofovir, NVP, draw Wei Pyridine, efavirenz, rilpivirine, drawing are for drawing Wei, Ai Weileiwei, Lopinavir, indinavir, Nai Feinawei, APV, profit Tuo Nawei, ACV, immunodepressant such as Mycophenolic Acid, cyclosporin, tacrolimus, sirolimus and pharmaceutically active peptides Class.
23. pharmaceutical compositions, its include therapeutically effective amount according to the compound of any one of claim 1 to 13,21 or 22 or Its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or diluent.
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